Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes
Open accessAbstract
An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1 high T cells, and IL17A+CD4+ T cells. Explanted grafts contained cells with a mature β cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.
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Upon graft removal, a majority of graft-derived cells immunostained for the general endocrine marker chromogranin A (CHGA).
“Upon graft removal, a majority of these graft-derived cells immunostained for the general endocrine marker chromogranin A (CHGA).”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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)
Experimental — accuracy not yet measuredFacilitating host-derived vascularization into the graft promoted long-term endocrine cell survival and function in humans.
“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.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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)
Experimental — accuracy not yet measuredIn other regions of the device, host fibroblasts were the predominant cell type, resulting in deposition of fibrotic tissue rather than host-derived vasculature.
“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.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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)
Experimental — accuracy not yet measuredObserved circulating C-peptide levels in these studies were too low to induce a measurable clinical benefit attributable to the transplanted cells.
“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.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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)
Experimental — accuracy not yet measuredThe porous design promoted the growth of host-derived blood vessels inside the device, and this phenomenon was more prominent in regions containing the graft-derived cells.
“As intended, the porous design promoted the growth of host-derived blood vessels inside the device, and this phenomenon was more prominent in regions containing the graft-derived cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
The Introduction describes portals designed to let capillaries enter the device, and the Results report blood vessels in explanted devices and endothelial staining adjacent to insulin-positive graft cells. The paper does not report that vascular growth was more prominent in regions containing graft-derived cells than elsewhere in the device. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In the ViaCyte clinical trial, explanted grafts after months in vivo were highly heterogenous between patients because the cells were transplanted as pancreatic progenitors and allowed to finish differentiating in vivo.
“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”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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)
Experimental — accuracy not yet measuredWhile there were regions of C-peptide positive β-like cells, a majority of the endocrine cells stained for the α cell marker glucagon; ductal cells and rare acinar cells were also observed.
“Interestingly, while there were regions of C-peptide positive β-like cells, a majority of these endocrine cells stained for the α cell marker glucagon. Ductal cells and rare acinar cells were also observed.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
The Results (page not provided) describe insulin-immunoreactive cells with a mature β-cell phenotype, an explanted endocrine population enriched in glucagon-positive cells, and scattered duct-like structures. They report few acinar cells in devices that were never implanted, but do not establish that acinar cells were rare in the explanted grafts or describe C-peptide-positive staining of β-like cells. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe transplanted PEC-Encap product was well tolerated with few adverse effects, but the trial was halted due to insufficient functional product engraftment.
“While the transplanted PEC-Encap product was well tolerated with few adverse effects, the trial was halted due to insufficient functional product engraftment.33”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
The Introduction (page unavailable) says the first 19 PEC-Encap recipients tolerated the product well with few complications. It also reports inconsistent cell survival and no evidence of insulin secretion, but does not say the trial was halted or give insufficient functional engraftment as the reason for halting it. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMacroencapsulation devices can promote fibrosis around the implant, further preventing nutrient diffusion.
“these macroencapsulation devices can also promote fibrosis around the implant, further preventing nutrient diffusion.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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)
Experimental — accuracy not yet measuredThese studies did not detect any serious safety concerns related to the transplanted cells, such as tumor formation.
“Importantly, these studies did not detect any serious safety concerns related to the transplanted cells, such as tumor formation.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
An ongoing clinical trial was started in 2017 at seven sites to test the PEC-Direct device (NCT03163511), and the first round of results have recently been published.
“An ongoing clinical trial was started in 2017 at seven sites to test this device (clinicaltrials.gov: NCT03163511), and the first round of results have recently been published.33,35”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
Some endocrine cells were observed, but fibrosis around the capsule resulted in graft loss, and no insulin secretion from the device was detected.
“While some endocrine cells were observed, fibrosis around the capsule resulted in graft loss, and no insulin secretion from the device was detected.33,34”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
The PEC-Direct trial demonstrated glucose responsive C-peptide production 6-9 months post-transplant as the grafted cells matured from pancreatic progenitors into pancreatic endocrine cells.
“They demonstrated glucose responsive C-peptide production 6-9 months post-transplant as the grafted cells matured from pancreatic progenitors into pancreatic endocrine cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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- Authors
- Ramzy, A., Thompson, D. M., Ward-Hartstonge, K. A., Ivison, S., Cook, L., Garcia, R. V., Loyal, J., Kim, P. T. W., Warnock, G. L., Levings, M. K., & Kieffer, T. J.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Kieffer, Timothy J.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 28
- Issue
- 12
- Pages
- 2047-2061.e5
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W3214753991
- Cited by
- 342
- References
- 55
- Citations by year
- 2026: 46 · 2025: 75 · 2024: 75 · 2023: 66 · 2022: 76 · 2021: 3 · 2012: 1
- FWCI
- 51.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Stem Cell Network
- California Institute for Regenerative Medicine
- Juvenile Diabetes Research Foundation United States of America
- BC Children’s Hospital
- Juvenile Diabetes Research Foundation Canada
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- type 1 diabetes, pluripotent stem cells, cell therapy, macroencapsulation, C-peptide secretion, glucose-dependent insulin secretion, beta cell differentiation, regulatory T cells, immunosuppression, graft safety, amylin, MafA
- MeSH terms
- C-Peptide, Cell Differentiation, Diabetes Mellitus, Type 1, Endoderm, Glucose, Humans, Insulin, Insulin-Secreting Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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