Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes

In the paper

“In 2014-15, several groups published protocols for generating stem cell-derived β (SC-β) cells that secreted insulin in response to glucose stimulation.36–38”

What the sources say

• Supported

  The Abstract describes a differentiation protocol that generates stem cell-derived β cells that secrete insulin in response to glucose. The Results section, “Generation of Glucose-Sensing Insulin-Secreting β Cells In Vitro,” reports their response to repeated glucose challenges. This 2014 paper supports the claim as one of the several cited protocols; page numbers were not provided. (LLM, conf=0.93)

  cites [36] Pagliuca FW, Millman JR, Gu M, Segel M, Dervort A. Van, Ryu JH, Peterson QP, Greiner D, and Melton DA (2014). Generation of functional human pancreatic ß-Cells in vitro. Cell 159, 428– 439. 25303535 PMC4617632 source
• ?Not checked — no full text of the sourcecites [37] Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O’Dwyer S, Quiskamp N, Mojibian M, Albrecht T, (2014). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol 32, 1121– 1133. 25211370 source
• Supported

  The Discussion describes this paper’s differentiation protocol and reports that its hESC-derived beta-like cells secreted insulin in response to increased glucose. It also notes two other groups’ 2014 reports of glucose-responsive beta-like cells. Together with this paper’s 2015 publication year, these passages support the claim that several groups published such protocols in 2014–15. (LLM, conf=0.93)

  cites [38] Russ HA, Parent AV, Ringler JJ, Hennings TG, Nair GG, Shveygert M, Guo T, Puri S, Haataja L, Cirulli V, (2015). Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 34, 1759– 1772. 25908839 PMC4516429 source

In the paper

“Their initial trial led to insulin independence of all seven patients 1 year after transplantation, vastly improving previous islet transplantation outcomes due to optimization of their immunosuppression regimen as well as benefiting from improvements in islet isolation techniques.”

What the sources say

• ?Not checked — no full text of the sourcecites [15] Shapiro J, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, and Rajotte RV (2000). Islet transplantation in seven patients with T1D using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med 343, 230– 238. 10911004 source
• Supported

  In “A new millennium begins,” the paper reports that all seven patients in the initial Edmonton Protocol cohort were insulin-independent at one year. It also describes substantially better results than earlier transplants and identifies changes in immunosuppression and islet processing as features of the protocol. (LLM, conf=0.94)

  cites [16] Bottino R, Knoll MF, Knoll CA, Bertera S, and Trucco MM (2018). The future of islet transplantation is now. Front. Med 5, 1– 13. PMC6053495 30057900 source

In the paper

“While the observed circulating C-peptide levels in these studies were too low to induce a measurable clinical benefit attributable to the transplanted cells, these clinical trials have demonstrated that facilitating host-derived vascularization into the graft promoted long-term endocrine cell survival and function in humans.”

What the sources say

• Partly supported

  The Discussion (page unavailable) says clinical improvements could not be clearly attributed to graft-derived C-peptide: outcomes did not differ between patients with higher and lower levels, and C-peptide secretion was likely not the major cause of improvement. But it does not establish that the levels were too low to produce any benefit; it suggests that some patients’ levels may be adequate for some clinical benefit. (LLM, conf=0.86)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion’s ‘Limitations of the study’ section reports measurable C-peptide but no statistically significant clinical benefit in this pilot study. It says the lack of benefit is *most likely* due to insufficient engrafted β-cell mass; the claim states more definitively that the circulating C-peptide levels were too low to cause a benefit and extends the finding to multiple studies. (LLM, conf=0.84)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 sourceExperimental — accuracy not yet measured

In the paper

“Upon graft removal, a majority of these graft-derived cells immunostained for the general endocrine marker chromogranin A (CHGA).”

What the sources say

• Partly supported

  The Results (page unavailable) report abundant synaptophysin-positive endocrine cell populations in explanted grafts. They do not report chromogranin A (CHGA) staining or establish that a majority of graft-derived cells stained for CHGA. (LLM, conf=0.82)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 sourceExperimental — accuracy not yet measured
• Supported

  The Results section, “Histology of explanted units” (page not provided), reports that chromogranin A-staining endocrine cells accounted for 66% of graft-derived cells. That is a majority, as the claim states. (LLM, conf=0.95)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 source

In the paper

“Not only are the number of pancreases available for islet isolation limited, but transplanting cells from multiple genetic backgrounds per patient could exacerbate immune rejection and graft failure.25,26”

What the sources say

• Partly supported

  The Introduction (page unavailable) says that islets from multiple donors are often needed and that HLA mismatches may lead to antibodies. The Discussion (page unavailable) links multiple mismatches to broad sensitization, but says the role of these antibodies in islet graft failure is difficult to prove. The paper therefore supports the immune-risk concern, not a demonstrated link from multiple donors to rejection and graft failure. (LLM, conf=0.84)

  cites [25] Campbell PM, Senior PA, Salam A, LaBranche K, Bigam DL, Kneteman NM, Imes S, Halpin A, Ryan EA, and Shapiro AMJ (2007). High risk of sensitization after failed islet transplantation. Am. J. Transplant 7, 2311– 2317. 17845564 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [26] Rickels MR, Kearns J, Markmann E, Palanjian M, Markmann JF, Naji A, and Kamoun M (2006). HLA sensitization in islet transplantation. Clin. Transplant, 413– 420. PMC4562323 18365398

In the paper

“In the ViaCyte clinical trial, the explanted grafts after months in vivo were observed to be highly heterogenous between patients since the cells were transplanted as pancreatic progenitors and allowed to finish differentiating in vivo.33,35”

What the sources say

• Partly supported

  The Results report heterogeneous grafts from 10 patients, examined 35–57 weeks after implantation. The Discussion says the implanted cells matured in patients. Neither passage establishes that transplanting progenitors to differentiate in vivo caused the differences between patients. (LLM, conf=0.84)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Histology of explanted units; page unavailable) describe explants collected 3–12 months after implantation and differences in their cellular and non-cellular regions. The Discussion says the implanted pancreatic progenitor cells differentiated and matured in vivo. Neither section establishes that differentiation caused the variation between patients; the Limitations section instead discusses variable engraftment and infiltration by host myofibroblasts. (LLM, conf=0.88)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 sourceExperimental — accuracy not yet measured

In the paper

“In other regions of the device, however, host fibroblasts were the predominant cell type, resulting in the deposition of fibrotic tissue rather than host-derived vasculature.”

What the sources say

• Partly supported

  The Results (page unavailable) report a background of fibrous tissue in all devices and substantial variation in graft cellularity. They do not identify host fibroblasts as the predominant cell type in particular regions or say that fibrosis developed there instead of host-derived vasculature; the Results also report blood vessels and direct vascularization into devices. (LLM, conf=0.82)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 sourceExperimental — accuracy not yet measured
• Supported

  The Results (Histology of explanted units) report that host-derived fibroblasts dominated regions where graft-derived cells were rare or absent. The Figure 3 description identifies collagenous fibers in regions associated with infiltrating host myofibroblasts and notes a paucity of blood-vessel staining there; the Results also report substantially lower vessel density in non-cellular regions. This supports the contrast with vascularized regions, though it does not mean vessels were entirely absent. (LLM, conf=0.91)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 source

In the paper

“They demonstrated glucose responsive C-peptide production 6-9 months post-transplant as the grafted cells matured from pancreatic progenitors into pancreatic endocrine cells.”

What the sources say

• Supported

  The Introduction identifies this as the PEC-Direct trial and says the implanted pancreatic endoderm cells matured into glucose-responsive insulin-secreting cells. The Results report meal-responsive C-peptide at 26 weeks (about six months), while the supplied passage describes rapid glucose-responsive C-peptide developing by 39 weeks (about nine months). (LLM, conf=0.91)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 source
• Supported

  The Introduction identifies the implanted PEC-01 product as PEC-Direct. The Discussion reports glucose-responsive C-peptide production and says the implanted pancreatic progenitors matured into insulin-secreting tissue over approximately 6–9 months. The Results clarify that detectable glucose-responsive C-peptide was observed in a subset of subjects, not all participants. (LLM, conf=0.93)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 source

In the paper

“Importantly, these studies did not detect any serious safety concerns related to the transplanted cells, such as tumor formation.”

What the sources say

• Supported

  The Summary reports that implants were well tolerated, with no teratoma formation or severe graft-related adverse events. The Results also report that pathological review of explanted devices found no evidence of teratoma formation. (LLM, conf=0.94)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 source
• Supported

  The Discussion reports no teratomas in the implanted units or evidence of metastatic growth outside the devices. The Results (Safety measures) report that investigators considered none of the serious adverse events related to VC-02, supporting the claim about serious safety concerns related to the transplanted cells. (LLM, conf=0.92)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 source

In the paper

“While the observed circulating C-peptide levels in these studies were too low to induce a measurable clinical benefit attributable to the transplanted cells, these clinical trials have demonstrated that facilitating host-derived vascularization into the graft promoted long-term endocrine cell survival and function in humans.”

What the sources say

• Partly supported

  The Introduction (page unavailable) describes devices designed to admit capillaries and reports that implanted cells survived and became functional in patients; the Results (page unavailable) confirm vascularization within the devices. The paper does not establish that vascularization itself promoted those outcomes: its limitations passage (labeled Abstract in our copy; page unavailable) says the uncontrolled trial cannot decisively determine the causal role of individual study components. (LLM, conf=0.86)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Histology of explanted units; page not provided) show host blood vessels entering the devices and greater vessel density in regions containing endocrine graft cells at 9–12 months. The Results also report engraftment and insulin expression through 12 months and responsive C-peptide through 24 months. These findings support long-term survival and function alongside vascularization, but do not establish that vascularization promoted them. (LLM, conf=0.84)

  cites [35] Shapiro AMJ, Thompson D, Donner TW, Bellin MD, Hsueh W, Pettus J, Wilensky J, Daniels M, Wang RM, Brandon EP, (2021). Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Reports Med. 2, 100466. PMC8714853 35028608 sourceExperimental — accuracy not yet measured

In the paper

“An initial 2014 human clinical trial (clinicaltrials.gov: NCT02239354) used the Encaptra device, which was designed to fully immunoprotect the cells using a cell-impermeable membrane.32”

What the sources say

• Partly supported

  The Introduction identifies Encaptra as the device used with VC-01 and says VC-01 was being tested in clinical trial NCT02239354. It describes a semipermeable barrier intended to potentially avoid immune suppression, but does not establish that the trial began in 2014, that it was the initial human trial, or that the device was designed to provide full immunoprotection. (LLM, conf=0.85)

  cites [32] Agulnick AD, Ambruzs DM, Moorman MA, Bhoumik A, Cesario RM, Payne JK, Kelly JR, Haakmeester C, Srijemac R, Wilson AZ, (2015). Insulin-producing endocrine cells dfifferentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl. Med 4, 1214– 1222. 26304037 PMC4572906 sourceExperimental — accuracy not yet measured

In the paper

“Improvements in whole pancreas transplantation since the 1960s demonstrated that donor pancreatic tissue could restore glucose homeostasis in diabetic patients.14”

What the sources say

• Supported

  The Conclusions date the first clinical pancreas transplant to 1966 and report that patient and graft survival improved over time. They also state that, while a graft functions, nearly all recipients are euglycemic and have normal glycosylated hemoglobin levels—supporting the claim that transplanted pancreatic tissue can restore glucose control in diabetic patients. Page numbers were not provided for these passages. (LLM, conf=0.93)

  cites [14] Sutherland DER, Gruessner RWG, Dunn DL, Matas AJ, Humar A, Kandaswamy R, Mauer SM, Kennedy WR, Goetz FC, Robertson RP, (2001). Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann. Surg 233, 463– 501. 11303130 PMC1421277 source

In the paper

“In particular, ViaCyte developed a stem cell-derived pancreatic endoderm cell population known as PEC-01, which they demonstrated to mature over several months in vivo into insulin-producing endocrine cells in rodent models.29–31”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG, Richardson M, Carpenter MK, D’Amour KA, Kroon E, (2011). Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat. Biotechnol 29, 750– 756. 21804561 source
• Partly supported

  The paper’s introductory discussion reports that ViaCyte transplanted hESC-derived pancreatic progenitors into mice and obtained mature, insulin-positive cells in vivo. It does not identify those cells as PEC-01 or specify that ViaCyte’s maturation took several months; the month-by-month results describe this paper’s own cells, not ViaCyte’s. (LLM, conf=0.83)

  cites [30] Rezania A, Bruin JE, Riedel MJ, Mojibian M, Asadi A, Xu J, Gauvin R, Narayan K, Karanu F, O’Neil JJ, (2012). Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61, 2016– 2029. 22740171 PMC3402300 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [31] Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, (2008). Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol 26, 443– 452. 18288110 source

In the paper

“These cells have been shown to improve glycemic control in diabetic mice, highlighting their potential utility in vivo.36,37,39–44”

What the sources say

• Supported

  The Results section, “Utility of Stem Cell-Derived β Cells for Treating Diabetes,” reports that transplanted SC-β cells reversed worsening hyperglycemia in diabetic NRG-Akita mice, unlike control cells. It also reports improved glucose clearance after a glucose injection, directly supporting the claim of improved glycemic control. (LLM, conf=0.94)

  cites [36] Pagliuca FW, Millman JR, Gu M, Segel M, Dervort A. Van, Ryu JH, Peterson QP, Greiner D, and Melton DA (2014). Generation of functional human pancreatic ß-Cells in vitro. Cell 159, 428– 439. 25303535 PMC4617632 source
• ?Not checked — no full text of the sourcecites [37] Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O’Dwyer S, Quiskamp N, Mojibian M, Albrecht T, (2014). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol 32, 1121– 1133. 25211370 source
• Supported

  The Results section (“A planar SC-β cell differentiation method”) reports that transplanted SC-β cells lowered fasting glucose in STZ-induced diabetic mice and restored glucose tolerance. It also reports that removing the grafts caused a rapid loss of glycemic control. (LLM, conf=0.95)

  cites [39] Hogrebe NJ, Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells. Nat. Biotechnol 38, 460– 470. 32094658 PMC7274216 source
• Supported

  The Results section, “Gene-corrected WS SC-β cells correct blood glucose in mice with pre-existing diabetes” (page not provided), reports that corrected SC-β cells normalized blood glucose and improved glucose tolerance after transplantation into diabetic mice. (LLM, conf=0.94)

  cites [40] Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, and Millman JR (2020). Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci. Transl. Med 12, eaax9106. 32321868 PMC7233417 source
• Supported

  The paper’s Abstract reports that transplanted, polymer-encapsulated SC-β cells maintained glycemic correction in diabetic mice for 174 days. This directly supports the claim that these cells have improved glycemic control in diabetic mice. (LLM, conf=0.94)

  cites [41] Vegas AJ, Veiseh O, Gürtler M, Millman JR, Pagliuca FW, Bader AR, Doloff JC, Li J, Chen M, Olejnik K, (2016). Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat. Med 22, 306– 311. 26808346 PMC4825868 source
• Supported

  The Results section, “Transplantation of SC-β Cells into Glucose-Intolerant Mice,” reports that diabetic mice treated with streptozotocin had greatly improved glucose tolerance 10 days after receiving the cells, compared with sham-treated diabetic mice. The Discussion likewise states that transplantation rapidly restored glucose tolerance and that function persisted for months. (LLM, conf=0.94)

  cites [42] Velazco-Cruz L, Song J, Maxwell KG, Goedegebuure MM, Augsornworawat P, Hogrebe NJ, and Millman JR (2019). Acquisition of dynamic function in human stem cell-derived β cells. Stem Cell Reports 12, 351– 365. 30661993 PMC6372986 source
• Supported

  The Results section (‘SC-islets control the glycemia of mice in vivo’) reports that grafted SC-islets maintained glucose control after streptozotocin-induced loss of the mice’s own beta cells. Blood glucose rose sharply when the graft-bearing kidney was removed, supporting the claim that the cells controlled glycemia in diabetic mice. (LLM, conf=0.92)

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 source
• Supported

  The Results section (‘Rapid onset of eBC functionality in vivo within days of transplantation,’ Fig. 7c–d) reports that mice receiving stem-cell-derived β-cell clusters cleared glucose faster than comparison groups. It also reports that transplantation ameliorated hyperglycaemia in mice with streptozotocin-induced diabetes, supporting the claim of improved glycemic control. (LLM, conf=0.94)

  cites [44] Nair GG, Liu JS, Russ HA, Tran S, Saxton MS, Chen R, Juang C, Li M. Ian, Nguyen VQ, Giacometti S, (2019). Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells. Nat. Cell Biol 21, 263– 274. 30710150 PMC6746427 source

In the paper

“Interestingly, they also reported a novel CDX2+ β-cell precursor-like population in the human fetal pancreas that resembled SC-EC cells,”

What the sources say

• Supported

  The section ‘Identification of an “enterochromaffin cell-like” pre-β-cell population in human fetal pancreas’ identifies a novel CDX2+ β-cell precursor-like population. The Discussion says SC-ECs closely resemble a CDX2-expressing cell population in the fetal pancreas; Figure 4 describes the same resemblance. (LLM, conf=0.94)

  cites [74] Zhu H, Wang G, Kim D, Miller M, Goss G, Kovsky J, Harrington AR, Saunders D, Powers AC, Preissl S, (2022). Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes. BioRxiv, 1– 74. PMC10175223 37040771 source

In the paper

“Despite transcriptional improvements, SC-islets nonetheless had significantly reduced activity of metabolic pathways compared to primary islets.”

What the sources say

• Supported

  The Discussion (page unavailable) reports transcriptional changes during SC-islet maturation but says SC-islets have significantly lower TCA metabolite enrichment and weaker glucose-responsive metabolic coupling than primary islets. The Results section on mitochondrial glucose coupling (page unavailable) likewise finds a glucose-induced respiratory response in primary islets but not SC-islets. (LLM, conf=0.87)

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 source

In the paper

“Notably, the non-endocrine cell populations of ductal-like, acinar-like, and mesenchymal-like cells were derived from populations that retained expression of cell cycle-associated genes.”

What the sources say

• Supported

  The “Fates of non-endocrine cells” section (page not provided) says that non-endocrine cells retain expression of cell-cycle-associated genes and, during stage 6, split into populations expressing pancreatic acinar, mesenchymal, and ductal markers. (LLM, conf=0.94)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Notably, both studies also provided greater resolution of cellular heterogeneity by describing specific subpopulations of expected cell types.”

What the sources say

• Supported

  In “Chromatin accessibility and gene expression during SC-islet differentiation” (page not available), the paper identifies distinct pancreatic progenitor and endocrine progenitor populations. In “Insufficient activation of signal-dependent gene regulatory programs in SC-islets” (page not available), it resolves the β-cell population into four subclusters. These findings support the claim as it applies to this cited study; they do not establish what the other study found. (LLM, conf=0.92)

  cites [74] Zhu H, Wang G, Kim D, Miller M, Goss G, Kovsky J, Harrington AR, Saunders D, Powers AC, Preissl S, (2022). Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes. BioRxiv, 1– 74. PMC10175223 37040771 source
• Not checked yetcites [75] Augswornworawat P, Hogrebe NJ, Ishahak M, Marquez E, Maestas M, Schmidt M, Veronese-Paniagua D, Gale S, Miller J, Velazco-Cruz L, (2022). Defining the chromatin and transcriptional landscape of stem cell-derived islets. BioRxiv, 1– 59.

In the paper

“These cells have been subsequently identified in SC-islets generated from various differentiation protocols and stem cell lines by multiple groups.”

What the sources say

• Partly supported

  In Results (‘SC-islets present organotypic cytoarchitecture and function’), Balboa et al. report SC-EC cells in islets made with their optimized protocol. In Results (‘SC-islets transcriptionally mature in vitro and in vivo’), they compare those cells with SC-EC cells identified by Veres et al., supporting identification by more than one group using different protocols. Methods lists several stem cell lines used in the study, but the passages do not establish that SC-EC cells were identified in islets from each line. (LLM, conf=0.82)

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports that this study used a different hESC line and seven-stage protocol from earlier single-cell studies, yet found the same EC-like endocrine population. The Results also identify an enterochromaffin population in its differentiated cells, consistent with another recent study. (LLM, conf=0.90)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 source
• Supported

  The Results (Retrieval and Identification of SC-Islet Cell Populations after Transplantation; page unavailable) identify SC-EC cells in this study’s SC-islets and report their earlier identification by Veres et al. The study used both hESC and hiPSC lines, while its Results describe SC-EC cells as arising from SC-islet differentiation protocols, supporting the claim’s broad wording. (LLM, conf=0.86)

  cites [51] Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Single-cell transcriptome profiling reveals β cell maturation in stem cell-derived islets after transplantation. Cell Rep. 32, 108067. 32846125 PMC7491368 source

In the paper

“Current protocols also produce a significant percentage of stem cell-derived enterochromaffin cells (SC-ECs), which resemble a type of intestinal endocrine.47”

What the sources say

• Partly supported

  The ‘SC-islets contain four major cell types’ section identifies SC-EC cells as a major population in both modified protocols and says they most resemble enterochromaffin cells. The ‘SC-EC cells’ section suggests their presence in other β-cell protocols, but does not establish that those protocols produce a significant percentage of them. (LLM, conf=0.82)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 sourceExperimental — accuracy not yet measured

In the paper

“The multiomic studies described here further demonstrated that SC-β cells were less similar to their primary counterparts than other stem cell-derived endocrine cell types.”

What the sources say

• Supported

  The section “Insufficient activation of signal-dependent gene regulatory programs in SC-islets” states that SC-β-cells clustered separately from primary β-cells, unlike non-β endocrine cell types. It explicitly concludes that SC-β-cells are more distant from their primary counterparts than other stem cell-derived endocrine cell types. (LLM, conf=0.94)

  cites [74] Zhu H, Wang G, Kim D, Miller M, Goss G, Kovsky J, Harrington AR, Saunders D, Powers AC, Preissl S, (2022). Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes. BioRxiv, 1– 74. PMC10175223 37040771 source
• Not checked yetcites [75] Augswornworawat P, Hogrebe NJ, Ishahak M, Marquez E, Maestas M, Schmidt M, Veronese-Paniagua D, Gale S, Miller J, Velazco-Cruz L, (2022). Defining the chromatin and transcriptional landscape of stem cell-derived islets. BioRxiv, 1– 59.

In the paper

“Despite distinguishable differences in gene expression between SC-EC and SC-β cells, the two populations appear to have a relatively similar overall transcriptional profile.”

What the sources say

• Supported

  The Discussion (page not specified) describes SC-EC cells as closely related to, but distinct from, SC-β cells. The SC-EC cells section identifies genes that distinguish the populations, supporting the claim that they are broadly similar despite expression differences. (LLM, conf=0.90)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Importantly, both studies indicated that epigenetic regulators are important drivers of cell identity, particularly in the cell fate choice between SC-EC and SC-β cells.”

What the sources say

• Partly supported

  In “Chromatin accessibility and gene expression during SC-islet differentiation” (page unavailable), the paper analyzes the SC-β/SC-EC lineage branch and identifies candidate transcription factors for each fate. The Discussion (page unavailable) describes these as predicted regulators, not demonstrated drivers, and the passages do not establish that epigenetic regulators specifically drive the fate choice. This source also cannot substantiate the statement about both studies on its own. (LLM, conf=0.82)

  cites [74] Zhu H, Wang G, Kim D, Miller M, Goss G, Kovsky J, Harrington AR, Saunders D, Powers AC, Preissl S, (2022). Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes. BioRxiv, 1– 74. PMC10175223 37040771 sourceExperimental — accuracy not yet measured
• Not checked yetcites [75] Augswornworawat P, Hogrebe NJ, Ishahak M, Marquez E, Maestas M, Schmidt M, Veronese-Paniagua D, Gale S, Miller J, Velazco-Cruz L, (2022). Defining the chromatin and transcriptional landscape of stem cell-derived islets. BioRxiv, 1– 59.

In the paper

“Despite the use of different pluripotent stem cell lines and protocols, both roadmaps observed well-known markers of pancreatic progenitors (e.g., PDX1, NKX6-1) during the middle stages of differentiation as well as islet-specific endocrine identity markers in their final cell populations (e.g., INS for β cells, GCG for α cells, SST for δ cells).”

What the sources say

• Supported

  The ‘SC-islets contain four major cell types’ section identifies PDX1+ progenitors at stage 3 and NKX6.1+ progenitors at stage 4, followed by INS-expressing SC-β cells and GCG-expressing α-like cells at stages 5–6. The ‘SC-β cells stably maintain identity’ section also reports a small stage-6 population of SST+HHEX+ cells resembling δ cells. The paper supports these observations for its own roadmap; it does not need to establish the findings of the other roadmap cited in the sentence. (LLM, conf=0.90)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, the current differentiation methodologies still produce off-target cell types, notably cells that resemble a type of intestinal endocrine called the enterochromaffin cell.47”

What the sources say

• Supported

  The Discussion states that directed β-cell differentiation protocols produce other cells alongside β cells. The ‘SC-islets contain four major cell types’ section identifies one such population as endocrine cells that most resemble enterochromaffin cells. (LLM, conf=0.94)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Using a semi-supervised method to construct a lineage tree of cell fate, it was demonstrated that divergent cell populations that arose during early stages did not significantly contribute to the off-target populations observed later.”

What the sources say

• Supported

  The Results section, ‘Reconstruct a lineage tree for the highly branched pancreatic differentiation process’ (Fig. 1b; page not provided), describes the semi-supervised lineage-tree method and states that divergent populations in early stages S0–S3 do not contribute to undesired populations at final stage S7. That supports the claim’s more cautious wording, ‘did not significantly contribute.’ (LLM, conf=0.94)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 source

In the paper

“Additionally, the other study identified CDX2 as the earliest transcription factor expressed during SC-EC lineage specification.”

What the sources say

• Supported

  The section ‘Establishment of SC-islet cell type lineage trajectories’ explicitly states that CDX2 was the earliest transcription factor expressed during SC-EC lineage specification. The citing sentence closely paraphrases that statement. (LLM, conf=0.95)

  cites [74] Zhu H, Wang G, Kim D, Miller M, Goss G, Kovsky J, Harrington AR, Saunders D, Powers AC, Preissl S, (2022). Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes. BioRxiv, 1– 74. PMC10175223 37040771 source

In the paper

“One attractive method is to encapsulate the cells in a device with finely controlled pore size that facilitates the diffusion of small molecules like glucose and insulin but blocks immune cells from infiltrating the device.52”

What the sources say

• Supported

  In “Strategies to maintain cell viability” (page not provided), the paper says pore size can be engineered to control which molecules pass through a membrane and that immune cells cannot pass through submicron or nanometre-sized channels. It also describes an encapsulation device as allowing insulin secretion in response to blood glucose while serving as an immune barrier. (LLM, conf=0.93)

  cites [52] Desai T, and Shea LD (2017). Advances in islet encapsulation technologies. Nat. Rev. Drug Discov 16, 338– 350. 28008169 PMC11286215 source

In the paper

“In subsequent stages, high expression of PDX1 in combination with expression of NKX6-1 and PTF1A was predictive of endocrine induction potential.”

What the sources say

• Supported

  In “The origin and lineage of SC-β cells,” the paper identifies stage-4 progenitors with NKX6–1+, PTF1A+, and PDX1high expression as marking an axis of variation that predicts endocrine induction potential. It also reports NEUROG3 expression at that end of the progenitor gradient on stage-5 day 1. (LLM, conf=0.94)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Of note, NOTCH signaling via HES1 was implicated as a driver of a non-endocrine fate.”

What the sources say

• Supported

  In the Results section (‘Switch genes mark cell fate choice and guide the improvement of differentiation protocol’), the paper identifies HES1 as a non-endocrine switch gene and a downstream target of NOTCH signaling that inhibits endocrine lineage development. It also reports higher NOTCH expression in the non-endocrine lineage and improved endocrine differentiation after HES1 deletion, supporting the claim that this pathway was implicated in non-endocrine fate choice. (LLM, conf=0.93)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 source

In the paper

“SC-β cells and off-target SC-EC cells appear to emerge from a common NEUROG3+ progenitor population.”

What the sources say

• Supported

  In “The origin and lineage of SC-β cells,” the authors state that their analysis suggests SC-β and SC-EC cells emerge from a common NEUROG3+ induction intermediate. The claim preserves the paper’s tentative wording. (LLM, conf=0.95)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Specifically, known markers of β cell maturation, such as INS, MAFA, IAPP, MNX1, and G6PC2, became more highly expressed in a greater proportion of SC-islet cells after transplantation.”

What the sources say

• Partly supported

  The Results section, “SC-islets transcriptionally mature in vitro and in vivo” (page unavailable), reports that IAPP rose upon engraftment and MAFA rose six months after engraftment; it also reports an increasing proportion of cells in more mature β-cell categories. But INS and G6PC2 increased early in vitro, not specifically after transplantation. The cited passages do not report post-transplant upregulation of MNX1 or an increased proportion of cells expressing each listed marker. (LLM, conf=0.89)

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 sourceExperimental — accuracy not yet measured
• Partly supported

  In Results, “SC-β Cells Mature within Transplanted Grafts” (page unavailable), the paper reports higher expression in a greater fraction of grafted SC-β cells for INS, MAFA, MNX1, and G6PC2. It also reports increased IAPP transcript after transplantation, but does not explicitly say IAPP was expressed in a greater fraction of cells. The finding is specific to SC-β cells, rather than SC-islet cells generally. (LLM, conf=0.83)

  cites [51] Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Single-cell transcriptome profiling reveals β cell maturation in stem cell-derived islets after transplantation. Cell Rep. 32, 108067. 32846125 PMC7491368 sourceExperimental — accuracy not yet measured

In the paper

“In contrast, the final non-endocrine off-target populations, including duct-like and pancreatic stellate-like cells, branched during pancreatic progenitor stages.”

What the sources say

• Supported

  The Results section identifies S4 as the pancreatic progenitor stage. In its lineage-tree analysis, a side branch from S4-C contributes to all final-stage (S7) non-endocrine populations, explicitly including PSC-like and duct-like cells. (LLM, conf=0.94)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 source

In the paper

“Interestingly, both scRNA-seq roadmaps detected significant cell diversification following the pancreatic progenitor stages.”

What the sources say

• Supported

  In ‘SC-islets contain four major cell types,’ the paper reports a single pancreatic-progenitor population at stage 3, followed by distinct endocrine and non-endocrine populations at stages 5 and 6. It states that this pattern appeared in both modified protocols. This supports the diversification attributed to this source; the other roadmap is not assessed here. (LLM, conf=0.90)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source
• Partly supported

  In Results, “A time-series single cell transcriptomic atlas during pancreatic β cell differentiation” (page unavailable), the paper says its cultures were relatively homogeneous before the pancreatic progenitor stage and much more heterogeneous later. It also reports cell populations found in an independent scRNA-seq dataset, but does not establish that both roadmaps detected diversification specifically after the pancreatic progenitor stage. (LLM, conf=0.83)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 sourceExperimental — accuracy not yet measured

In the paper

“After sequencing 40,444 cells during the second half of SC-islet differentiation, the first study reported a mostly homogeneous population of PDX1+ progenitors at end of stage 3.”

What the sources say

• Supported

  In “SC-islets contain four major cell types,” the paper reports sequencing 40,444 cells sampled from the end of stage 3 through stage 6. It also says that stage-3 cells in both modified protocols comprised a single population of PDX1+ pancreatic progenitors, supporting the description as mostly homogeneous. (LLM, conf=0.93)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Using canonical gene markers of islet cell types, both multiomic studies identified distinct populations representing SC-β, SC-α, SC-δ, and SC-EC cells.”

What the sources say

• Supported

  In “Chromatin accessibility and gene expression during SC-islet differentiation,” the paper says it annotated cell populations using canonical genes and identified distinct SC-α, SC-β, SC-δ, and SC-EC populations in both snATAC-seq and scRNA-seq data. This confirms the finding attributed to this source; the passage does not need to establish what the other cited study found. (LLM, conf=0.94)

  cites [74] Zhu H, Wang G, Kim D, Miller M, Goss G, Kovsky J, Harrington AR, Saunders D, Powers AC, Preissl S, (2022). Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes. BioRxiv, 1– 74. PMC10175223 37040771 source
• Not checked yetcites [75] Augswornworawat P, Hogrebe NJ, Ishahak M, Marquez E, Maestas M, Schmidt M, Veronese-Paniagua D, Gale S, Miller J, Velazco-Cruz L, (2022). Defining the chromatin and transcriptional landscape of stem cell-derived islets. BioRxiv, 1– 59.

In the paper

“To this end, significant progress has been made at improving the function of SC-islets when compared to the original protocols,39,40,44,48,49”

What the sources say

• Supported

  The Results section ('A planar SC-β cell differentiation method') reports improved dynamic glucose-stimulated insulin secretion with the planar protocol compared with the authors’ earlier suspension protocol for two cell lines (Fig. 4i). It also reports faster diabetes reversal after transplantation in mice (Fig. 5a). These functional improvements support the citing sentence’s broad claim. (LLM, conf=0.90)

  cites [39] Hogrebe NJ, Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells. Nat. Biotechnol 38, 460– 470. 32094658 PMC7274216 source
• Supported

  The Introduction (page not provided) contrasts earlier approaches, whose patient-derived SC-β cells showed only modest function, with a newer differentiation protocol producing highly functional cells. The Results (page not provided) also report improved insulin secretion after gene correction. Together, these passages support the broad claim of progress in SC-islet function, although they do not report a head-to-head comparison with the original protocols. (LLM, conf=0.86)

  cites [40] Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, and Millman JR (2020). Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci. Transl. Med 12, eaax9106. 32321868 PMC7233417 source
• Supported

  The Discussion (page not provided) says earlier differentiation protocols omitted endocrine-cell clustering and that adding a reaggregation step gave stem-cell-derived β cells enhanced functional properties. The Results (page not provided) identify the pre-reaggregation cells as closely resembling the end-stage cells of earlier protocols, supporting the comparison. (LLM, conf=0.91)

  cites [44] Nair GG, Liu JS, Russ HA, Tran S, Saxton MS, Chen R, Juang C, Li M. Ian, Nguyen VQ, Giacometti S, (2019). Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells. Nat. Cell Biol 21, 263– 274. 30710150 PMC6746427 source
• ?Could not verify

  The supplied passage and the indexed passages have no substantive discussion of SC-islet function or comparisons with original protocols; they consist largely of links. Searches for insulin secretion, maturation, and original protocols did not retrieve a passage that establishes the claimed improvement. (LLM, conf=0.72)

  cites [48] Alvarez-Dominguez JR, Donaghey J, Rasouli N, Kenty JHR, Helman A, Charlton J, Straubhaar JR, Meissner A, and Melton DA (2020). Circadian entrainment triggers maturation of human in vitro islets. Cell Stem Cell 26, 108– 122.e10. 31839570 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [49] Mahaddalkar PU, Scheibner K, Pfluger S, Sterr M, Beckenbauer J, Irmler M, Beckers J, Knöbel S, and Lickert H (2020). Generation of pancreatic beta cells from CD177+ anterior definitive endoderm. Nat. Biotechnol 38, 1061– 1072. 32341565 source

In the paper

“SC-islets are generated through a multistep differentiation process that attempts to mimic stages of embryonic development with the timed application of growth factors and small molecules, driving stem cells through several intermediate cell types on their way to becoming pancreatic endocrine cells (Figure 2).57”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [57] Hogrebe NJ, Maxwell KG, Augsornworawat P, and Millman JR (2021). Generation of insulin-producing pancreatic β cells from multiple human stem cell lines. Nat. Protoc 16, 4109– 4143. 34349281 PMC8529911 source

In the paper

“The second report sequenced 87,769 cells across 12 points during the differentiation of a stem cell line known to result in highly heterogeneous SC-islets.”

What the sources say

• Supported

  The Results section, “A time-series single cell transcriptomic atlas during pancreatic β cell differentiation,” reports profiling 87,769 cells across 12 time points during differentiation of H1 cells and says the cultures became much more heterogeneous at later stages. The Abstract identifies H1 as a relatively low-efficiency stem-cell line chosen for its increased cellular heterogeneity. Page numbers are not provided in our copy. (LLM, conf=0.95)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 source

In the paper

“SC-islets generated in vitro remain transcriptionally and functionally immature compared to adult human islets.”

What the sources say

• Partly supported

  The Discussion says earlier hPSC-derived β-like cells appeared immature in transcript and functional analyses. But it also reports that the paper’s reaggregated cells gained adult-islet-like functional properties; although some adult β-cell markers and insulin output remained lower, the unqualified claim that in-vitro-generated SC-islets remain functionally immature overstates the paper’s findings. No page numbers are provided in our copy. (LLM, conf=0.86)

  cites [44] Nair GG, Liu JS, Russ HA, Tran S, Saxton MS, Chen R, Juang C, Li M. Ian, Nguyen VQ, Giacometti S, (2019). Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells. Nat. Cell Biol 21, 263– 274. 30710150 PMC6746427 sourceExperimental — accuracy not yet measured
• Partly supported

  Figure 3 reports that in vitro hPSC-derived insulin-expressing cells resemble fetal rather than adult β cells in gene expression and appear functionally immature, lacking glucose-stimulated insulin secretion. The study compares sorted insulin-expressing cells with adult β cells isolated from islets; it does not establish the same finding for SC-islets as a whole compared with whole adult islets. (LLM, conf=0.83)

  cites [77] Hrvatin S, O’Donnell CW, Deng F, Millman JR, Pagliuca FW, DiIorio P, Rezania A, Gifford DK, and Melton DA (2014). Differentiated human stem cells resemble fetal, not adult, β cells. Proc. Natl. Acad. Sci 111, 3038– 3043. 24516164 PMC3939927 sourceExperimental — accuracy not yet measured
• Supported

  The ‘Differences between SC-islets and adult cadaveric islets’ section says in-vitro SC-islets differ from cadaveric islets in RNA transcripts and full function. It also reports reduced glucose-stimulated insulin secretion in vitro and further maturation after transplantation. Page numbers were not supplied. (LLM, conf=0.91)

  cites [78] Melton D. (2021). The promise of stem cell-derived islet replacement therapy. Diabetologia 64, 1030– 1036. 33454830 PMC8012315 source

In the paper

“scRNA-seq analysis of transplanted SC-islets revealed that improved function corresponded with transcriptional maturation.”

What the sources say

• Supported

  The Results section reports scRNA-seq analysis of SC-islet grafts retrieved after transplantation and identifies transcriptional maturation during engraftment. The Discussion explicitly says that maturation-marker expression after implantation correlated with improved in vivo function (page not specified in our copy). (LLM, conf=0.93)

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 source
• Supported

  The Discussion says the authors used scRNA-seq to characterize transcriptome changes in transplanted, functionally improved SC-islets. It reports that grafted SC-β cells acquired expression of adult β-cell maturation markers, including MAFA and G6PC2. (LLM, conf=0.94)

  cites [51] Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Single-cell transcriptome profiling reveals β cell maturation in stem cell-derived islets after transplantation. Cell Rep. 32, 108067. 32846125 PMC7491368 source

In the paper

“and recent advances in single-cell sequencing technologies have allowed for unprecedented characterization of these cells to further elucidate ways to refine SC-β cell differentiation strategies.43,47,50,51”

What the sources say

• Supported

  The Results section describes single-cell RNA sequencing across stages of SC-islet differentiation and engraftment to characterize cell populations and maturation. The Discussion explicitly says knowledge from these single-cell analyses could lead to improved differentiation protocols. (LLM, conf=0.92)

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 source
• Supported

  The Discussion says the study uses single-cell RNA sequencing to comprehensively characterize cells formed during SC-β-cell differentiation and presents the analysis as a resource for improving differentiation protocols. The Purification of endocrine and SC-β cells section also reports a concrete refinement identified from the sequencing data: a way to enrich SC-β cells. (LLM, conf=0.93)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source
• Supported

  The Abstract reports single-cell profiling of 95,308 cells across β-cell differentiation and says the resulting lineage analysis provided insights that led to improved differentiation protocols. The Results section describes how the profiling characterized cell populations across differentiation stages. (LLM, conf=0.93)

  cites [50] Weng C, Xi J, Li H, Cui J, Gu A, Lai S, Leskov K, Ke L, Jin F, and Li Y (2020). Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat. Metab 2, 1443– 1458. 33257854 PMC7744443 source
• Supported

  The Introduction says the authors use single-cell RNA sequencing to characterize SC-islet cells and describes the resulting data as a resource for advancing directed differentiation technologies. The Discussion says their characterization of transcriptome changes in transplanted SC-β cells had not previously been explored and could inform further SC-β-cell generation. Page numbers are not provided in our copy. (LLM, conf=0.90)

  cites [51] Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Single-cell transcriptome profiling reveals β cell maturation in stem cell-derived islets after transplantation. Cell Rep. 32, 108067. 32846125 PMC7491368 source

In the paper

“Biomaterials may also be fabricated with instructive chemistry to induce local immune tolerance around the transplanted cells.53”

What the sources say

• Supported

  The section “Reducing encapsulated-cell death and material immunogenicity” says that tailoring biomaterial properties, including chemical structure, can make immune cells at the implant site more tolerogenic. The Conclusions likewise describe materials designed to provide local cues that shift responding cells toward a regulatory phenotype. Page numbers were not supplied. (LLM, conf=0.90)

  cites [53] Samojlik MM, and Stabler CL (2021). Designing biomaterials for the modulation of allogeneic and autoimmune responses to cellular implants in Type 1 Diabetes. Acta Biomater. 133, 87– 101. 34102338 PMC9148663 source

In the paper

“Furthermore, primary islets often demonstrated progressive functional decline in the years following transplantation, necessitating patients to resume exogenous insulin injections overtime.”

What the sources say

• Supported

  The Abstract reports an inexorable decline in insulin independence for up to eight years after transplantation, and the Concluding Remarks say insulin-independence rates fell markedly by years three and five. This supports the claim that many recipients eventually need insulin again, though the paper notes that islet function can persist after insulin independence is lost. (LLM, conf=0.89)

  cites [124] McCall M, and Shapiro AMJ (2012). Update on islet cell transplantation. Cold Spring Harb Perspect Med 2, a007823. 22762022 PMC3385934 source

In the paper

“For example, in contrast to prior studies, it was recently reported that PD-L1 alone was not sufficient to protect against xeno- and allorejection in transplanted SC-islets.”

What the sources say

• Partly supported

  The Results (Engineering immune-evasive SC-islet cells; page unavailable) report that PD-L1 overexpression did not protect transplanted SC-islets from xenorejection in the authors’ mouse model. The paper does not establish the same result for transplanted allografts; the Discussion says PD-L1 may still be useful in an allogeneic setting. (LLM, conf=0.90)

  cites [54] Gerace D, Zhou Q, Kenty JH, Boulanger KR, Li H, Melton DA, Gerace D, Zhou Q, Kenty JH, Veres A, (2023). Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance. Cell Reports Med. 4, 100879. PMC9873825 36599351 sourceExperimental — accuracy not yet measured

In the paper

“Similarly, alginate microcapsules designed to release exosomes derived from umbilical cord mesenchymal stem cells were also shown to induce local immune tolerance by altering signaling in multiple immune cell types.”

What the sources say

• Supported

  The Discussion (page unavailable) describes an alginate platform that releases umbilical cord MSC exosomes and reduces inflammation around islet xenotransplants. The Results (page unavailable) report suppressed T-cell responses and altered macrophage NFκB activity, supporting the claim’s description of local immunomodulation across immune cell types. (LLM, conf=0.88)

  cites [109] Mohammadi MR, Rodriguez SM, Luong JC, Li S, Cao R, Alshetaiwi H, Lau H, Davtyan H, Jones MB, Jafari M, (2021). Exosome loaded immunomodulatory biomaterials alleviate local immune response in immunocompetent diabetic mice post islet xenotransplantation. Commun. Biol 4, 1– 17. 34083739 PMC8175379 source

In the paper

“The main cause of rejection in allogeneic transplantation is T-cell recognition of human leukocyte antigens (HLAs).”

What the sources say

• ?Could not verify

  No passage from our copy matched the claim, and searches for allogeneic transplantation, HLA, T cells, and rejection returned no passages. The available text therefore does not establish whether the paper identifies T-cell recognition of HLAs as the main cause of rejection. (LLM, conf=0.70)

  cites [117] Bluestone JA, and Tang Q (2020). Solving the Puzzle of Immune Tolerance for β-Cell Replacement Therapy for Type 1 Diabetes. Cell Stem Cell 27, 505– 507. 33007232 sourceExperimental — accuracy not yet measured

In the paper

“To this end, PD-L1111 or FasL112,113 proteins were immobilized onto the surface of poly(ethylene glycol) microgels, which were then mixed together with allogeneic islets and co-transplanted into either mice111,112 or non-human primates113. In conjunction with a transient rapamycin treatment, these functionalized microgels greatly improved islet survival without the need for long-term immunosuppres”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [111] Coronel MM, Martin KE, Hunckler MD, Barber G, O’Neill EB, Medina JD, Opri E, McClain CA, Batra L, Weaver JD, (2020). Immunotherapy via PD-L1-presenting biomaterials leads to long-term islet graft survival. Sci. Adv 6, 1– 15. PMC7455180 32923626 source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [112] Headen DM, Woodward KB, Coronel MM, Shrestha P, Weaver JD, Zhao H, Tan M, Hunckler MD, Bowen WS, Johnson CT, (2018). Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance. Nat. Mater 17, 732– 739. 29867165 PMC6060019 source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [113] Lei J, Coronel MM, Yolcu ES, Deng H, Grimany-Nuno O, Hunckler MD, Ulker V, Yang Z, Lee KM, Zhang A, (2022). FasL microgels induce immune acceptance of islet allografts in nonhuman primates. Sci. Adv 8, 1– 15. PMC9106299 35559682 source

In the paper

“this study highlights that relying on active fluid flow rather than passive diffusion for nutrient transport can greatly enhance the viability and performance of islets within a macroencapsulation device.”

What the sources say

• Supported

  The Results (ceMED Design and Investigation of Optimal Loading Conditions; page numbers not supplied) contrast convection-driven nutrient delivery with the limitations of passive diffusion and predict improved islet survival and insulin secretion with flow. The Discussion reports that flow was crucial for islet survival and function in the prevascular phase, while noting that the in vivo assessment ended at 30 days. (LLM, conf=0.94)

  cites [94] Yang K, O’Cearbhaill ED, Liu SS, Zhou A, Chitnis GD, Hamilos AE, Xu J, Verma MKS, Giraldo JA, Kudo Y, (2021). A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion. Proc. Natl. Acad. Sci 118, 1– 12. PMC8449352 34504013 source
• Partly supported

  The Results sections on rodent islet viability and human islet culture report better viability and preserved insulin responses with continuous flow than with static culture. The Discussion says improved nutrient delivery is a likely explanation, but notes that flow may have other effects. The experiments used an in vitro microphysiological chip with alginate-embedded islets, not a macroencapsulation device, so that device-specific extension is not established. (LLM, conf=0.86)

  cites [95] Patel SN, Ishahak M, Chaimov D, Velraj A, LaShoto D, Hagan DW, Buchwald P, Phelps EA, Agarwal A, and Stabler CL (2021). Organoid microphysiological system preserves pancreatic islet function within 3D matrix. Sci. Adv 7, eaba5515. 33579705 PMC7880596 sourceExperimental — accuracy not yet measured

In the paper

“This stress response is thought to be involved in the progression of both type 1 and type 2 diabetes.”

What the sources say

• Supported

  The “ER stress in T1DM and T2DM” section states that evidence indicates ER stress contributes to β-cell failure in both types of diabetes. The paper defines the ER stress response in the same section. Page numbers were not provided in our copy. (LLM, conf=0.94)

  cites [130] Eizirik DL, Pasquali L, and Cnop M (2020). Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat. Rev. Endocrinol 16, 349– 362. 32398822 source

In the paper

“These gene-edited cells were co-transplanted with allogenic mouse islets to reverse diabetes significantly longer than without the genetic modifications.”

What the sources say

• Supported

  The Introduction identifies the engineered mesenchymal stromal cells as overexpressing PD-L1 and CTLA4-Ig and says that co-transplanted allogeneic islets corrected diabetes for up to 100 days, versus rejection by day 20 with unmodified MSCs. The Results section reports significantly longer islet-graft survival with engineered MSCs than with native MSCs (P < 0.0001). (LLM, conf=0.94)

  cites [116] Wang X, Wang K, Yu M, Velluto D, Hong X, Wang B, Chiu A, Melero-Martin JM, Tomei AA, and Ma M (2022). Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression. Sci. Adv 8, 1– 17. PMC9307254 35867788 source

In the paper

“Early investigation of primary human islet transplants56 and animal studies122,123 demonstrated that 50% or more of the islet graft was lost during the first few days after transplantation.”

What the sources say

• ?Not checked — no full text of the sourcecites [56] Eich T, Eriksson O, and Lundgren T (2007). Visualization of early engraftment in clinical islet transplantation by positron-emission tomography. N. Engl. J. Med 356, 2754– 2755. 17596618 source
• ?Not checked — no full text of the sourcecites [122] Eich T, Eriksson O, Sundin A, Estrada S, Brandhorst D, Brandhorst H, Langstrom B, Nilsson B, Korsgren O, and Lundgren T (2007). Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model. Transplantation 84, 893– 898. 17984843 source
• Supported

  The Discussion reports that 60% of the initially transplanted β-cell mass was lost by day 3 in an animal transplantation model. This supports the animal-study portion of the sentence; the human-transplant portion is attached to a different citation. (LLM, conf=0.91)

  cites [123] Biarnés M, Montolio M, Nacher V, Raurell M, Soler J, and Montanya E (2002). β-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia. Diabetes 51, 66– 72. 11756324 source

In the paper

“These gene-edited iPSCs could differentiate into endothelial cells and cardiomyocytes that demonstrated long-term survival in humanized mouse models without any immunosuppression.”

What the sources say

• Supported

  The paper reports that B2M−/−CIITA−/− CD47-overexpressing human iPSCs were differentiated into endothelial-like cells and cardiomyocyte-like cells. In the Results passage indexed under Abstract (page unavailable), both types of graft survived for 50 days in allogeneic humanized mice; a subsequent passage states that engineered derivatives survived long-term without immunosuppression. (LLM, conf=0.93)

  cites [118] Deuse T, Hu X, Gravina A, Wang D, Tediashvili G, De C, Thayer WO, Wahl A, Garcia JV, Reichenspurner H, (2019). Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat. Biotechnol 37, 252– 258. 30778232 PMC6419516 source

In the paper

“Importantly, HLA-E expression in hPSCs has been demonstrated to inhibit killing by NK cells.”

What the sources say

• Supported

  The Results section (‘HLA-E SC expression prevents NK-mediated lysis’) reports that HLA-E expression reversed increased NK-cell lysis of cells derived from engineered human ESCs. The experiments measured differentiated CD45+ cells, rather than a reduction in lysis of undifferentiated ESCs. (LLM, conf=0.90)

  cites [120] Gornalusse GG, Hirata RK, Funk SE, Riolobos L, Lopes VS, Manske G, Prunkard D, Colunga AG, Hanafi LA, Clegg DO, (2017). HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat. Biotechnol 35, 765– 772. 28504668 PMC5548598 source

In the paper

“Rat islets encapsulated within the device were able to survive and reverse diabetes in immune-competent diabetic mice.”

What the sources say

• Supported

  The Abstract reports that the thread-reinforced device protected encapsulated rat islets in immunocompetent C57BL/6 mice and corrected chemically induced diabetes for three months. It also reports functional islets in devices retrieved from cured mice. The paper notes that cell survival was not directly measured in the initial four-week experiment, so the claim should not be read as a measured survival rate. (LLM, conf=0.92)

  cites [101] An D, Chiu A, Flanders JA, Song W, Shou D, Lu Y, Grunnet LG, and Winkel L (2017). Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc. Natl. Acad. Sci 115, E263– E272. 29279393 PMC5777032 source

In the paper

“In both these examples, the oxygen generated by the device significantly enhanced the viability and function of the islets after transplantation.”

What the sources say

• Partly supported

  The Results section on the diabetic mouse model reports improved viability and insulin response in OxySite devices after transplantation, but the transplanted devices contained MIN6 beta cells, not pancreatic islets. The paper reports improved rat and human islet viability and function in vitro; it does not establish those outcomes for islets after transplantation. It also describes one oxygen-generating approach, so it cannot substantiate “both” examples on its own. (LLM, conf=0.89)

  cites [98] Coronel MM, Liang JP, Li Y, and Stabler CL (2019). Oxygen generating biomaterial improves the function and efficacy of beta cells within a macroencapsulation device. Biomaterials 210, 1– 11. 31029812 PMC6527135 sourceExperimental — accuracy not yet measured
• Supported

  The Results section reports better post-transplant islet survival and insulin expression in oxygen-generating iBED devices than in controls. It also reports significantly better engraftment and glucose regulation in mice. These findings support the claim for this paper’s device. (LLM, conf=0.90)

  cites [99] Wang L-H, Ernst AU, Flanders JA, Liu W, Wang X, Datta AK, Epel B, Kotecha M, Papas KK, and Ma M (2021). An inverse-breathing encapsulation system for cell delivery. Sci. Adv 7, 5835– 5849. PMC8121434 33990318 source

In the paper

“Lastly, in a unique approach, scRNA-seq and a CRIPSR screen of SC-islets transplanted into a humanized mouse model revealed that SC-islets upregulated genes in the interferon (IFN) pathway during graft rejection.”

What the sources say

• Supported

  The Results (Figure 1 description) report scRNA-seq and a whole-genome CRISPR screen of SC-islet grafts in a humanized mouse model, with grafts analyzed after PBMC-associated failure. The Discussion states that SC-islets responding to allogeneic immune cells strongly upregulate interferon-stimulated genes. (LLM, conf=0.92)

  cites [121] Sintov E, Nikolskiy I, Barrera V, Hyoje-Ryu Kenty J, Atkin AS, Gerace D, Ho Sui SJ, Boulanger K, and Melton DA (2022). Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets. Stem Cell Reports 17, 1976– 1990. 36055241 PMC9481918 source

In the paper

“these macroencapsulation devices can also promote fibrosis around the implant, further preventing nutrient diffusion.”

What the sources say

• Partly supported

  The Introduction (page unavailable) identifies device fibrosis as a cause of cell loss, and the Results report fibrous tissue in explanted devices. A separate passage discusses nutrient diffusion across large distances, but the paper does not specifically say that fibrosis around the implant prevents nutrient diffusion. (LLM, conf=0.82)

  cites [33] Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, (2021). Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28, 2047– 2061. 34861146 sourceExperimental — accuracy not yet measured
• Supported

  In “Bounding into the Clinic” (page not provided), the paper reports that cells in a semi-permeable implant often die after a fibrotic reaction on the device exterior. “Stealth Mode” describes fibrotic scar tissue choking off encapsulated cells, while the macroencapsulation discussion explains that larger devices create a greater barrier to oxygen delivery. Together, these passages support the claim that fibrosis around such implants can further impede nutrient access. (LLM, conf=0.86)

  cites [34] Dolgin E. (2016). Encapsulating the problem. Nature 540, S60– 62. 27926697 source
• Partly supported

  The Results report that implanted TheraCyte encapsulation devices were encased in fibrotic tissue. The paper does not report that this fibrosis prevented nutrient diffusion, so the proposed consequence is unsupported. (LLM, conf=0.88)

  cites [91] Matveyenko AV, Georgia S, Bhushan A, and Butler PC (2010). Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats. Am. J. Physiol. - Endocrinol. Metab 299, 713– 720. PMC3774125 20587750 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Safety evaluation; page not specified) report fibrotic tissue surrounding the implanted βAir device. The Introduction and Discussion explain that encapsulated islets depend on diffusion for nutrient delivery, but do not say that the surrounding fibrosis further impeded that diffusion. (LLM, conf=0.86)

  cites [92] Carlsson PO, Espes D, Sedigh A, Rotem A, Zimerman B, Grinberg H, Goldman T, Barkai U, Avni Y, Westermark GT, (2018). Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus. Am. J. Transplant 18, 1735– 1744. 29288549 PMC6055594 sourceExperimental — accuracy not yet measured

In the paper

“This PD-L1 strategy was pushed even further by directly overexpressing PD-L1 in islet-like organoids made from hiPSCs using a lentiviral system.67 These engineered cells were found to evade the immune system in both immune-competent mice and in a humanized mouse model.”

What the sources say

• Supported

  The Methods section says PD-L1-expressing hiPSCs were generated with a lentivirus, and the ‘PD-L1 provides immune protection for HILOs’ section says they were differentiated into organoids. That section reports sustained graft function in immune-competent diabetic mice and in a mouse model with a reconstituted human T-cell repertoire. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [67] Yoshihara E, O’Connor C, Gasser E, Wei Z, Oh TG, Tseng TW, Wang D, Cayabyab F, Dai Y, Yu RT, (2020). Immune-evasive human islet-like organoids ameliorate diabetes. Nature 586, 606– 611. 32814902 PMC7872080 source

In the paper

“Knockout of CXCL10, which is induced by IFN signaling and appeared to be essential for early IFN-triggered immune responses in transplanted SC-islets, improved survival during allogeneic transplantation in humanized mice.”

What the sources say

• Supported

  The Results section (“CXCL10-deficient SC-islets are hypoimmunogenic in vivo”) reports that CXCL10-deficient grafts remained functional while wild-type grafts failed after human PBMC injection, and explicitly describes improved SC-islet survival. Another Results passage links CXCL10 to IFNγ induction and early alloimmune responses. The claim concerns graft survival, not survival of the mice. (LLM, conf=0.94)

  cites [121] Sintov E, Nikolskiy I, Barrera V, Hyoje-Ryu Kenty J, Atkin AS, Gerace D, Ho Sui SJ, Boulanger K, and Melton DA (2022). Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets. Stem Cell Reports 17, 1976– 1990. 36055241 PMC9481918 source

In the paper

“For instance, a network of interconnected hydrophobic channels inside an islet-filled alginate hydrogel greatly increased the diffusion of oxygen throughout the device from the surrounding tissue.”

What the sources say

• Supported

  The Discussion describes continuous air channels within a hydrophobic scaffold incorporated into an islet-containing alginate hydrogel. The Results explain that oxygen from the surrounding environment rapidly permeates those channels throughout the device, improving oxygenation of islets far from its surface. (LLM, conf=0.93)

  cites [100] Wang LH, Ernst AU, An D, Datta AK, Epel B, Kotecha M, and Ma M (2021). A bioinspired scaffold for rapid oxygenation of cell encapsulation systems. Nat. Commun 12, 1– 16. 34615868 PMC8494927 source

In the paper

“Because of this major cell loss during the immediate aftermath of transplantation, a high islet mass from multiple organ donors and several infusions was used in the clinic.”

What the sources say

• Supported

  The SINGLE-DONOR ISLET TRANSPLANTATION section says that up to 60% of islet mass can be lost in the first few days after infusion and that a larger islet mass delivered over multiple infusions leaves more surviving cells. It also says most recipients receive islets from multiple donors (average 2–3), supporting the clinical practice described. (LLM, conf=0.94)

  cites [124] McCall M, and Shapiro AMJ (2012). Update on islet cell transplantation. Cold Spring Harb Perspect Med 2, a007823. 22762022 PMC3385934 source

In the paper

“Interestingly, they also observed a decreased fibrotic response with their active fluid flow setup.”

What the sources say

• Supported

  The Results section ('Transplantation of Glucose-sensing, Insulin-secreting Cells within the ceMED') reports a lower fibrotic response in infused devices than in static, no-flow devices, including less fibrotic tissue around the membrane. The Discussion likewise says fibrosis was significantly thinner while convection was in place. (LLM, conf=0.94)

  cites [94] Yang K, O’Cearbhaill ED, Liu SS, Zhou A, Chitnis GD, Hamilos AE, Xu J, Verma MKS, Giraldo JA, Kudo Y, (2021). A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion. Proc. Natl. Acad. Sci 118, 1– 12. PMC8449352 34504013 source

In the paper

“Another group added a zwitterioinic modification to alginate microcapsules to significantly reduce fibrosis due to its ability to resist protein adsorption and cell attachment.”

What the sources say

• Partly supported

  The Results (Development of zwitterionically modified alginates; Zwitterionically modified alginates mitigate CO in mice) report reduced protein adsorption and significantly reduced cell adhesion. The Results (FBR mitigation in dogs and pigs) describe thinner fibrous tissue around modified capsules, but say this fibrosis-related finding was qualitative and lacked a statistical comparison. The Discussion treats reduced protein adsorption as a likely contributor to reduced cellular overgrowth, while saying the exact mechanisms need further study; the claim overstates both the significance of the fibrosis finding and the certainty of its cause. (LLM, conf=0.87)

  cites [106] Liu Q, Chiu A, Wang LH, An D, Zhong M, Smink AM, de Haan BJ, de Vos P, Keane K, Vegge A, (2019). Zwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation. Nat. Commun 10, 1– 14. 31748525 PMC6868136 sourceExperimental — accuracy not yet measured

In the paper

“For example, a combinatorial biomaterial screen identified three different triazole-containing covalent modifications to alginate that significantly reduced the foreign body response in both rodents and non-human primates.”

What the sources say

• Supported

  The Abstract describes a combinatorial approach to covalently modify alginate and reports three triazole-containing analogs that substantially reduced foreign body reactions in rodents and non-human primates. No page number is provided for the passage. (LLM, conf=0.94)

  cites [104] Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K, (2016). Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol 34, 345– 352. 26807527 PMC4904301 source

In the paper

“Instead, they reported HLA depletion facilitated improved cell survival.”

What the sources say

• Supported

  The Results section on delayed graft rejection reports that, after mismatched PBMC injection in humanized mice, WT SC-islet grafts were destroyed within two weeks while rejection of HLA-deficient B2M−/− grafts was delayed. Some B2M−/− graft function remained at seven weeks. The improvement was temporary; the authors expected eventual rejection. (LLM, conf=0.88)

  cites [54] Gerace D, Zhou Q, Kenty JH, Boulanger KR, Li H, Melton DA, Gerace D, Zhou Q, Kenty JH, Veres A, (2023). Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance. Cell Reports Med. 4, 100879. PMC9873825 36599351 source

In the paper

“These studies utilizing modified alginate chemistries point to an interesting shift in thinking whereby a biomaterial is not only thought of as a physical barrier to keep out immune cells but rather as a source of instructive signals to induce local immune tolerance,”

What the sources say

• Supported

  The Conclusions and Future Recommendations section contrasts encapsulation as a barrier to immune-cell attack with biomaterials that provide instructive cues to suppress immune activation or promote a regulatory phenotype. The section on active and local immunomodulation also describes combining alginate encapsulation with CXCL12 to improve graft survival, consistent with the claimed shift toward local immune modulation. Page numbers were not available in our copy. (LLM, conf=0.90)

  cites [84] Samojlik MM, and Stabler CL (2021). Designing biomaterials for the modulation of allogeneic and autoimmune responses to cellular implants in Type 1 Diabetes. Acta Biomater. 133, 87– 101. 34102338 PMC9148663 source

In the paper

“Insulin secretion and blood glucose control was also enhanced when transplanted into diabetic rats.”

What the sources say

• Supported

  The Results section, “Transplantation of Glucose-sensing, Insulin-secreting Cells within the ceMED to Restore Glycemic Control,” reports lower blood glucose and improved glucose tolerance in diabetic rats receiving the perfused device compared with no-flow controls. The same section reports a 3.9-fold increase in human insulin in the flow group after transplantation with primary human islets. (LLM, conf=0.93)

  cites [94] Yang K, O’Cearbhaill ED, Liu SS, Zhou A, Chitnis GD, Hamilos AE, Xu J, Verma MKS, Giraldo JA, Kudo Y, (2021). A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion. Proc. Natl. Acad. Sci 118, 1– 12. PMC8449352 34504013 source

In the paper

“The development of local rather than systemic immune tolerance was further highlighted by the transplantation of a second set of unmodified, donor matched cells that survived when grafted to the original transplantation site but were rejected when transplanted to the other kidney of the same mouse.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [114] Yolcu ES, Zhao H, Bandura-Morgan L, Lacelle C, Woodward KB, Askenasy N, and Shirwan H (2011). Pancreatic islets engineered with SA-FasL protein establish robust localized tolerance by inducing regulatory T cells in mice. J. Immunol 187, 5901– 5909. 22068235 PMC3232043 sourceExperimental — accuracy not yet measured
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [115] Woodward KB, Zhao H, Shrestha P, Batra L, Tan M, Grimany-Nuno O, Bandura-Morgan L, Askenasy N, Shirwan H, and Yolcu ES (2020). Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long-term graft-localized immune privilege. Am. J. Transplant 20, 1285– 1295. 31850658 PMC7299172 source

In the paper

“Overexpression of CD47 has also been successfully implemented to mitigate innate immune responses after HLA deletion.”

What the sources say

• Supported

  The paper reports that HLA I/II-depleted human iPSC derivatives had significantly increased CD47 expression (Abstract; page not provided). It also reports that Cd47-overexpressing, MHC-deficient mouse derivatives resisted innate immune clearance, unlike counterparts without Cd47 overexpression (Abstract; page not provided). (LLM, conf=0.93)

  cites [118] Deuse T, Hu X, Gravina A, Wang D, Tediashvili G, De C, Thayer WO, Wahl A, Garcia JV, Reichenspurner H, (2019). Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat. Biotechnol 37, 252– 258. 30778232 PMC6419516 source

In the paper

“Overall, comparison of scRNA-seq and snATAC-seq data from transplanted SC-islets and primary islets has indicated that SC-islets become more similar to human islets overtime in vivo in terms of both their transcriptional and chromatin accessibility profiles, though some important differences still remain.”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [43] Balboa D, Barsby T, Lithovius V, Saarimäki-Vire J, Omar-Hmeadi M, Dyachok O, Montaser H, Lund PE, Yang M, Ibrahim H, (2022). Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. Nat. Biotechnol 40, 1042– 1055. 35241836 PMC9287162 sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [51] Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Single-cell transcriptome profiling reveals β cell maturation in stem cell-derived islets after transplantation. Cell Rep. 32, 108067. 32846125 PMC7491368 sourceExperimental — accuracy not yet measured
• Not checked yetcites [75] Augswornworawat P, Hogrebe NJ, Ishahak M, Marquez E, Maestas M, Schmidt M, Veronese-Paniagua D, Gale S, Miller J, Velazco-Cruz L, (2022). Defining the chromatin and transcriptional landscape of stem cell-derived islets. BioRxiv, 1– 59.

In the paper

“This initial cell death of transplanted cells can also cause release of molecules that initiate other immune responses, further exacerbating the issue by causing other transplanted cells to exhibit stress responses.”

What the sources say

• Partly supported

  The Introduction (page unavailable) says dying cells release DAMPs that activate innate immune cells and induce inflammation. The Summary and concluding remarks says neighboring cells can show different responses to stress, but does not establish that molecules released by dying cells cause stress responses in other cells. The paper does not address this proposed chain of events in transplanted cells. (LLM, conf=0.85)

  cites [141] Sachet M, Liang YY, and Oehler R (2017). The immune response to secondary necrotic cells. Apoptosis 22, 1189– 1204. 28861714 PMC5630647 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [142] De Vos P, Lazarjani HA, Poncelet D, and Faas MM (2014). Polymers in cell encapsulation from an enveloped cell perspective. Adv. Drug Deliv. Rev 67–68, 15– 34. 24270009 source

In the paper

“In the context of SC-islet differentiation, SC-EC cells are one of the most common off-targets.”

What the sources say

• Supported

  The ‘SC-islets contain four major cell types’ section identifies SC-EC cells as one of the major populations at stages 5 and 6, distinct from the intended SC-β cells. Extended Data Table 2 also lists SC-EC cells as a core population found in all datasets from stage 5 onward. The paper does not give a precise frequency ranking, but its classification supports ‘one of the most common off-targets.’ (LLM, conf=0.88)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 source

In the paper

“Substantial genomic variation has also been observed specifically in hiPSCs,167 particularly for BCOR mutations that are involved in many cancers.168”

What the sources say

• Supported

  The Results section on genomic heterogeneity reports substantial variation between hiPSC lines. The Results section on recurrent BCOR mutations reports BCOR mutations in hiPSCs and notes that such mutations have also been reported in hematological malignancies and several other cancers. No page numbers are available in our copy. (LLM, conf=0.91)

  cites [167] Rouhani FJ, Zou X, Danecek P, Badja C, Amarante TD, Koh G, Wu Q, Memari Y, Durbin R, Martincorena I, (2022). Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells. Nat. Genet 54, 1406– 1416. 35953586 PMC9470532 source
• Supported

  Citation 168 supports the claim about BCOR mutations and cancer: the Abstract says BCOR alterations recur in a large variety of tumors, and the Conclusion describes somatic alterations across many tumor subtypes. The separate claim about genomic variation in hiPSCs is attached to citation 167, not this source. (LLM, conf=0.93)

  cites [168] Astolfi A, Fiore M, Melchionda F, Indio V, Bertuccio SN, and Pession A (2019). BCOR involvement in cancer. Epigenomics 11, 835– 855. 31150281 PMC6595546 source

In the paper

“Correcting this stress-causing pathogenic variant with CRISPR/Cas9, however, allowed this iPSC line to generate highly functional SC-islets that were capable of rapidly reversing severe diabetes in mice, illustrating that gene-editing strategies can be used to mitigate stress responses.”

What the sources say

• Supported

  The Discussion states that CRISPR/Cas9 correction of the pathogenic WFS1 variant in patient-derived iPSCs produced functional SC-β cells that rapidly rescued mice with severe pre-existing diabetes. It also reports reduced ER and mitochondrial stress after correction, supporting the sentence’s point about mitigating stress responses. (LLM, conf=0.94)

  cites [40] Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, and Millman JR (2020). Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci. Transl. Med 12, eaax9106. 32321868 PMC7233417 source

In the paper

“Variants can be acquired through standard culture of the cells and reprogramming.163”

What the sources say

• Supported

  The Introduction reports genomic aberrations absent from the original fibroblast line and distinguishes those arising during reprogramming from those accumulating during long-term passage. The Discussion also describes accumulation of genetic aberrations during culture of human pluripotent stem cell lines. (LLM, conf=0.93)

  cites [163] Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, (2011). Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106– 118. 21211785 PMC3043464 source

In the paper

“Of greatest concern is the potential for highly proliferative uncommitted progenitors or residual hPSCs to be present in the final SC-islet product that have the potential to form tumors.158–160”

What the sources say

• Partly supported

  The Introduction (page unavailable) says residual pluripotent stem cells can persist after differentiation and cause tumors upon implantation. The Discussion (page unavailable) reports tumor formation after transplantation of differentiated mouse stem-cell populations. The paper does not establish tumor risk from highly proliferative uncommitted progenitors or specifically examine a final human SC-islet product. (LLM, conf=0.85)

  cites [158] Millman JR, Tan JH, and Colton CK (2021). Mouse pluripotent stem vell differentiation under physiological oxygen reduces residual teratomas. Cell. Mol. Bioeng 14, 555– 567. 34900010 PMC8630352 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [159] Fong CY, Gauthaman K, and Bongso A (2010). Teratomas from pluripotent stem cells: A clinical hurdle. J. Cell. Biochem 111, 769– 781. 20665544 source
• ?Not checked — no full text of the sourcecites [160] Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, Shim SH, Rhee YH, Lee SH, Oh SJ, Lee MY, (2013). Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc. Natl. Acad. Sci. U. S. A 110, 3281– 3290. PMC3761568 23918355 source

In the paper

“For example, SC-islets differentiated from iPSCs generated from a patient with Wolfram syndrome, which is characterized by ER stress, exhibited poor function and increased stress responses.40”

What the sources say

• Supported

  In the Results section on glucose-stimulated insulin secretion, unedited Wolfram syndrome patient iPSC-derived SC-β cells had poorer insulin secretion than gene-corrected cells. The Results section on ER and mitochondrial stress reports increased stress-marker expression in the unedited cells. Page numbers were not supplied. (LLM, conf=0.93)

  cites [40] Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, and Millman JR (2020). Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci. Transl. Med 12, eaax9106. 32321868 PMC7233417 source

In the paper

“These often take the form of an inducible gene to encoded for a protein that kills the cell, such as inducible Caspase9172 or proliferation-induced constructs.173”

What the sources say

• Partly supported

  The Introduction (page unavailable) describes HSV-TK as a suicide-gene system whose ablation is limited to cells with high proliferative potential, supporting the existence of proliferation-dependent safety switches. But this paper tests inducible caspase-9, not a proliferation-induced construct, so it does not support presenting its own system as the latter example. (LLM, conf=0.79)

  cites [172] Itakura G, Kawabata S, Ando M, Nishiyama Y, Sugai K, Ozaki M, Iida T, Ookubo T, Kojima K, Kashiwagi R, (2017). Fail-safe system against potential tumorigenicity after transplantation of iPSC derivatives. Stem Cell Reports 8, 673– 684. 28262544 PMC5355810 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [173] Liang Q, Monetti C, Shutova MV, Neely EJ, Hacibekiroglu S, Yang H, Kim C, Zhang P, Li C, Nagy K, (2018). Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 563, 701– 704. 30429614 source

In the paper

“and six specific variants in TP53 have been identified in several hPSC lines.165”

What the sources say

• Supported

  The paper reports identifying six TP53 mutations in five unrelated hESC lines; hESCs are a type of hPSC. It also says all six were confirmed by droplet digital PCR. (LLM, conf=0.94)

  cites [165] Merkle FT, Ghosh S, Kamitaki N, Mitchell J, Avior Y, Mello C, Kashin S, Mekhoubad S, Ilic D, Charlton M, (2017). Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545, 229– 233. 28445466 PMC5427175 source

In the paper

“Notably, these bioreactors allow for real-time monitoring and culture of critical process parameters, such as dissolved oxygen, that will be critical for quality control during large-scale production.”

What the sources say

• Partly supported

  The Carbon dioxide/osmolality section discusses monitoring dissolved CO₂ and controlling it independently of dissolved oxygen in large-scale culture; it also notes that an online CO₂ instrument is available. The pH control section describes probes used during cultivation. These passages support monitoring and control of culture conditions, but do not establish real-time dissolved-oxygen monitoring or its role in production quality control. (LLM, conf=0.82)

  cites [177] Nienow AW (2006). Reactor engineering in large scale animal cell culture. Cytotechnology 50, 9– 33. 19003068 PMC3476006 sourceExperimental — accuracy not yet measured

In the paper

“Assuming a similar dose as with human islets from deceased donors,175,176 on the order of 109 cells will be required per patient.”

What the sources say

• ?Not checked — no full text of the sourcecites [175] Markmann JF, Deng S, Huang X, Desai NM, Velidedeoglu EH, Lui C, Frank A, Markmann E, Palanjian M, Brayman K, (2003). Insulin independence following isolated islet transplantation and single islet infusions. Ann. Surg 237, 741– 750. 12796569 PMC1514687 source
• Partly supported

  The transplant procedures section says the islets came from deceased donors, and the transplant outcomes section reports a mean dose of 850,035 islet equivalents per patient. The paper does not express that dose as cells or establish that approximately 10^9 cells are required per patient. Page numbers are not provided in our copy. (LLM, conf=0.85)

  cites [176] Ryan EA, Lakey JRT, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, and Shapiro AMJ (2002). Successful islet transplantation. Diabetes 51, 2148– 2157. 12086945 sourceExperimental — accuracy not yet measured

In the paper

“SC-islet protocols that are performed completely in suspension culture36 benefit from the natural three-dimensional scaling of these systems.”

What the sources say

• Supported

  The Experimental Procedures (Cell culture; page not specified) describe maintaining the stem cells in spinner flasks and initiating differentiation from those cultures. The Introduction describes the protocol as a three-dimensional culture system, and the Discussion explicitly calls it scalable, reporting production of 300 million cells in suspension in one 500 ml flask. (LLM, conf=0.90)

  cites [36] Pagliuca FW, Millman JR, Gu M, Segel M, Dervort A. Van, Ryu JH, Peterson QP, Greiner D, and Melton DA (2014). Generation of functional human pancreatic ß-Cells in vitro. Cell 159, 428– 439. 25303535 PMC4617632 source

In the paper

“Hepatic, mesenchyme, and pancreatic exocrine are also possible off-targets reported from SC-islet differentiations47,51,75”

What the sources say

• Partly supported

  The “Fates of non-endocrine cells” section (page unavailable) reports cells differentiating toward pancreatic exocrine fates and populations expressing mesenchymal markers during SC-islet differentiation. It does not report hepatic off-target cells, so this source supports only part of the list. (LLM, conf=0.88)

  cites [47] Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Quinn P, Poh Y, Sintov E, Gürtler M, Charting cellular identity during human in vitro β - cell differentiation. Nature, 368– 373. PMC6903417 31068696 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “Retrieval and Identification of SC-Islet Cell Populations after Transplantation” (page unavailable), reports exocrine cells among the cell types found in SC-islet samples. The passages from our copy do not identify hepatic or mesenchyme cells as off-targets; searches for “hepatic” and “mesenchyme” found no supporting passage. (LLM, conf=0.86)

  cites [51] Augsornworawat P, Maxwell KG, Velazco-Cruz L, and Millman JR (2020). Single-cell transcriptome profiling reveals β cell maturation in stem cell-derived islets after transplantation. Cell Rep. 32, 108067. 32846125 PMC7491368 sourceExperimental — accuracy not yet measured
• Not checked yetcites [75] Augswornworawat P, Hogrebe NJ, Ishahak M, Marquez E, Maestas M, Schmidt M, Veronese-Paniagua D, Gale S, Miller J, Velazco-Cruz L, (2022). Defining the chromatin and transcriptional landscape of stem cell-derived islets. BioRxiv, 1– 59.

In the paper

“Alternatively, islets embedded within sub-millimeter collagen cylinders coated with endothelial cells154 or islets combined with microvascular fragments155 were demonstrated to become rapidly vascularized and connected to the host vasculature when transplanted into rodents.”

What the sources say

• Supported

  Citation 154 attaches to the endothelial-coated collagen-cylinder approach, not the separate microvascular-fragment approach cited as 155. The paper describes submillimeter collagen modules coated with endothelial cells and reports that rat islets embedded in them became revascularized and integrated with host vasculature by day 14 after subcutaneous transplantation into mice (Modular Tissue Engineering and Islet Transplantation; Conclusion). (LLM, conf=0.93)

  cites [154] Vlahos AE, Cober N, and Sefton MV (2017). Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. Proc. Natl. Acad. Sci. U. S. A 114, 9337– 9342. 28814629 PMC5584405 source
• Supported

  Citation 155 supports the microvascular-fragment part of the sentence, not the collagen-cylinder approach assigned to citation 154. In Results, ‘In vivo vascularization of prevascularized murine islet organoids,’ the authors report accelerated vascularization after transplantation into mice and attribute early blood perfusion to interconnection of the fragments with surrounding microvasculature. (LLM, conf=0.93)

  cites [155] Nalbach L, Roma LP, Schmitt BM, Becker V, Körbel C, Wrublewsky S, Pack M, Später T, Metzger W, Menger MM, (2021). Improvement of islet transplantation by the fusion of islet cells with functional blood vessels. EMBO Mol. Med 13, 1– 21. PMC7799357 33135383 source

In the paper

“In humans, several alternative transplantation sites to the liver have been proposed144, including the subcutaneous space145, intramuscular space146, and the omentum147,148.”

What the sources say

• Supported

  The citation is attached to the statement that alternatives to liver implantation have been proposed, not to the three sites cited separately afterward. The paper’s “Optimal site for islet implantation” section says that many implantation sites have been proposed, while noting that few have reached clinical use; its “Bone, muscle and fat” section discusses transplantation in human patients. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  cites [144] Merani S, Toso C, Emamaullee J, and Shapiro AMJ (2008). Optimal implantation site for pancreatic islet transplantation. Br. J. Surg 95, 1449– 1461. 18991254 source
• ?Not checked — no full text of the sourcecites [145] Pepper AR, Gala-Lopez B, Pawlick R, Merani S, Kin T, and Shapiro AMJ (2015). A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat. Biotechnol 33, 518– 523. 25893782 source
• Supported

  Citation 146 is attached to the intramuscular site, not to the subcutaneous space or omentum. The Results section reports pancreatic islet autotransplantation to the brachioradialis muscle in three human patients, confirming that muscle was investigated as an alternative to the liver. (LLM, conf=0.94)

  cites [146] Christoffersson G, Henriksnäs J, Johansson L, Rolny C, Ahlström H, Caballero-Corbalan J, Segersvärd R, Permert J, Korsgren O, Carlsson PO, (2010). Clinical and experimental pancreatic islet transplantation to striated muscle: Establishment of a vascular system similar to that in native islets. Diabetes 59, 2569– 2578. 20651296 PMC3279536 source

In the paper

“Transplanting these preconditioned SC-islets in combination with supplemental amino acids to mitigate nutrient deprivation drastically improved SC-islet survival within the first several weeks, highlighting how cell-targeted interventions can improve graft outcomes.”

What the sources say

• Supported

  The Results (‘Promoting SCIPC Survival after Transplant’) report that cells generated at 5% oxygen and transplanted with alanine and glutamine had significantly improved graft survival, with 75% surviving to day 20. The Discussion describes the combined approach as greatly improving survival and identifies nutrient deprivation as a contributor to graft loss. (LLM, conf=0.93)

  cites [143] Faleo G, Russ HA, Wisel S, Parent AV, Nguyen V, Nair GG, Freise JE, Villanueva KE, Szot GL, Hebrok M, (2017). Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant. Stem Cell Reports 9, 807– 819. 28803916 PMC5599226 source

In the paper

“Interestingly, it was demonstrated that ensuring the pancreatic progenitor population expressed the glycoprotein GP2 prevented tumor formation upon transplantation, suggesting that dangerous cell populations in the final cell product can potentially be identified earlier in the differentiation.161”

What the sources say

• Supported

  The Discussion states that sorting pancreatic progenitors for GP2 prevented teratoma formation. The Results section, “GP2 sorting prevents teratoma formation in vivo,” reports no outgrowths in mice transplanted with GP2-enriched cells. Page numbers were not supplied. (LLM, conf=0.94)

  cites [161] Aghazadeh Y, Sarangi F, Poon F, Nkennor B, McGaugh EC, Nunes SS, and Nostro MC (2022). GP2-enriched pancreatic progenitors give rise to functional beta cells in vivo and eliminate the risk of teratoma formation. Stem Cell Reports 17, 964– 978. 35364010 PMC9023812 source

In the paper

“To date, however, these alternative sites have yet to lead to improved transplant outcomes when compared to portal vein infusion in humans.149”

What the sources say

• Supported

  The Alternative transplantation sites section says that no clinically applicable site has yet been proven superior to the intraportal site. The procedure section also describes intraportal infusion as the gold standard and the only site reliably producing high rates of insulin independence in patients with type 1 diabetes. (LLM, conf=0.93)

  cites [149] Gamble A, Pepper AR, Bruni A, and Shapiro AMJ (2018). The journey of islet cell transplantation and future development. Islets 10, 80– 94. 29394145 PMC5895174 source

In the paper

“While 2-5 x 106 SC-islet cells are sufficient to reverse hyperglycemia in mice,150”

What the sources say

• Supported

  The Results section reports that transplanting 2 or 5 million SC-islet cells under the kidney capsule reversed diabetes in mice with pre-existing hyperglycemia. The claim matches those tested doses; the demonstrated effect is specific to that transplantation site. (LLM, conf=0.94)

  cites [150] Maxwell KG, Kim MH, Gale SE, and Millman JR (2022). Differential function and maturation of human stem cell-derived islets after transplantation. Stem Cells Transl. Med 11, 322– 331. 35294547 PMC8968674 source

In the paper

“These alternative sites may also potentially circumvent the intense IBMIR response that is observed with portal vein infusion.149”

What the sources say

• Supported

  The Alternative transplantation sites section says investigators have sought extrahepatic sites that might obviate IBMIR. The procedure section identifies intraportal infusion as the current implantation approach, supporting the sentence’s contrast with portal vein infusion. The claim is appropriately hedged as a possibility, not an established clinical outcome. (LLM, conf=0.94)

  cites [149] Gamble A, Pepper AR, Bruni A, and Shapiro AMJ (2018). The journey of islet cell transplantation and future development. Islets 10, 80– 94. 29394145 PMC5895174 source

In the paper

“Hypoxic conditions and oxidative stress can also induce other stress pathways that result in β cell functional failure and apoptosis.”

What the sources say

• ?Not checked — no full text of the sourcecites [131] Lazard D, Vardi P, and Bloch K (2012). Induction of beta-cell resistance to hypoxia and technologies for oxygen delivery to transplanted pancreatic islets. Diabetes. Metab. Res. Rev 28, 475– 484. 22389124 source
• ?Not checked — no full text of the sourcecites [132] Drews G, Krippeit-Drews P, and Duïfer M (2010). Oxidative stress and beta-cell dysfunction. Pflugers Arch. Eur. J. Physiol 460, 703– 718. 20652307 source
• Partly supported

  The Hypoxic Response section says hypoxia activates stress pathways beyond HIF, and Hypoxia-independent Activation of HIF says oxidative stress may activate HIF in β-cells and cause secretory dysfunction. The paper mentions apoptosis in connection with pro-inflammatory cytokines, but does not say that hypoxia- or oxidative-stress-induced pathways cause β-cell apoptosis. The indexed passages provide no page numbers. (LLM, conf=0.86)

  cites [133] Cantley J, Grey ST, Maxwell PH, and Withers DJ (2010). The hypoxia response pathway and β-cell function. Diabetes, Obes. Metab 12, 159– 167. 21029313 sourceExperimental — accuracy not yet measured
• Partly supported

  The “Oxidative Stress in β-Cell Dysfunction” section says oxidative stress can lead to ER stress and that ROS can activate pathways that trigger β-cell apoptosis. The Conclusions also link prolonged stress-pathway activation to β-cell dysfunction and death. The passages found do not address hypoxic conditions as a trigger, so that part of the claim is unsupported by our copy. (LLM, conf=0.84)

  cites [134] Kulkarni A, Muralidharan C, May SC, Tersey SA, and Mirmira RG (2022). Inside the β cell: molecular stress response pathways in diabetes pathogenesis. Endocrinology 164, 1– 15. PMC9667558 36317483 sourceExperimental — accuracy not yet measured

In the paper

“A fundamental challenge to scaling hPSC differentiation in suspension culture is the fluid convection necessary to keep cells from settling, which is made more difficult due to hPSCs requiring either microcarriers or culture in aggregates.178”

What the sources say

• Partly supported

  The Agitation section (page unavailable) says stirring keeps aggregates or microcarriers suspended and that shear can damage cells on them, supporting the stated scale-up challenge. But the paper also identifies encapsulation as a suspension-culture mode, so it does not support the categorical claim that hPSCs require either microcarriers or aggregates. (LLM, conf=0.85)

  cites [178] Kehoe DE, Jing D, Lock LT, Tzanakakis ES, and Ph D (2010). Scalable stirred-suspension bioreactor culture. Tissue Eng. Part A 16, 405– 421. 19739936 PMC2813185 sourceExperimental — accuracy not yet measured

In the paper

“Development of a large-scale, cost-efficient manufacturing methodology for differentiating SC-islets will be necessary to make this therapy available to a substantial number of patients.174”

What the sources say

• Partly supported

  The Methods sections on scale of manufacturing and cost-of-goods modeling compare production at 50 and 500 doses per year and estimate lower per-dose costs at the higher volume. But the Discussion section on efficient treatment delivery cautions that high-volume production must be weighed against demand, clinical capacity, and the cells’ short shelf life. The paper does not establish that a large-scale, cost-efficient differentiation method is necessary to make SC-islets available to a substantial number of patients; it models pancreatic-progenitor implants rather than fully differentiated SC-islets. (LLM, conf=0.84)

  cites [174] Wallner K, Pedroza RG, Awotwe I, Piret JM, Senior PA, Shapiro AMJ, and McCabe C (2018). Stem cells and beta cell replacement therapy: A prospective health technology assessment study. BMC Endocr. Disord 18, 1– 12. 29382312 PMC5791348 sourceExperimental — accuracy not yet measured

In the paper

“Similar to primary islet infusion, transplantation of SC-islets into mice has demonstrated that a significant portion of the cells can die shorty after transplantation due to the synergistic effects of nutrient deprivation and hypoxia.143”

What the sources say

• Partly supported

  The Results section, “Attrition of SCIPC and Mature Islet Grafts after Transplant,” reports that approximately 50% of SCIPC graft mass was lost within one week of transplantation into mice. The Results section, “Impact of Hypoxia on SCIPC and Islet Viability,” shows synergistic cell death from nutrient deprivation and hypoxia in vitro. The Discussion says these factors are likely major contributors to death after transplantation, but does not demonstrate that their synergy caused the observed loss in mice. (LLM, conf=0.83)

  cites [143] Faleo G, Russ HA, Wisel S, Parent AV, Nguyen V, Nair GG, Freise JE, Villanueva KE, Szot GL, Hebrok M, (2017). Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant. Stem Cell Reports 9, 807– 819. 28803916 PMC5599226 sourceExperimental — accuracy not yet measured