Differentiated human stem cells resemble fetal, not adult, β cells
Open accessAbstract
Significance: Human pluripotent stem cells (hPSCs) can be produced from any person and have the potential to differentiate into any cell type in the body. This study focuses on the generation of insulin-expressing cells from hPSCs and compares their gene expression, as assayed by transcriptional gene products, to that of insulin-expressing β cells from human fetal and adult samples. We employ a new method to isolate and profile insulin-expressing cells and conclude that several different hPSC lines generate very similar insulin-expressing cells, cells whose transcripts resemble fetal rather than adult β cells. This study advances the possibility of directing the differentiation of stem cells into functional β cells by comparing and cataloging differences between hPSC-derived insulin-expressing cells and human β cells.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SC-islets generated in vitro remain transcriptionally and functionally immature compared to adult human islets.
“SC-islets generated in vitro remain transcriptionally and functionally immature compared to adult human islets.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [77]
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)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556 · see citing works
Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1393 · Cited by 1,843 · cited 1× · see citing works
“For example, pancreatic and duodenal homeobox 1 (PDX1), vmaf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), and NK6 homeobox 1 (NKX6-1) are markers of adult human β cells (17) and in vivo-matured hPSC-INS cells (22, 26).”
BackgroundGelling, R. W., Du, X. Q., Dichmann, D. S., Rømer, J., Huang, H., Cui, L., Obici, S., Tang, B., Holst, J. J., Fledelius, C., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237106100 · Cited by 563 · see citing works
Tissue-specific transcriptional regulation has diverged significantly between human and mouse
Odom, D. T., Dowell, R. D., Jacobsen, E. S., Gordon, W., Danford, T. W., MacIsaac, K. D., Rolfe, P. A., Conboy, C. M., Gifford, D. K., & Fraenkel, E. (2007) · Nature Genetics · doi:10.1038/ng2047 · Cited by 506 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 55
- Takahashi K, et al. (2007) Induction of pluripotent stem cells from adult human fi- broblasts by defined factors. Cell 131(5):861-872.
- Thomson JA, et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145-1147.
- Yu J, et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917-1920.
- Park I-H, et al. (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451(7175):141-146.
- Colman A, Dreesen O (2009) Pluripotent stem cells and disease modeling. Cell Stem Cell 5(3):244-247.
- Daley GQ (2010) Stem cells: Roadmap to the clinic. J Clin Invest 120(1):8-10.
- Rubin LL (2008) Stem cells and drug discovery: The beginning of a new era? Cell 132(4):549-552.
- Chin MH, et al. (2009) Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5(1):111-123.
- Doi A, et al. (2009) Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41(12):1350-1353.
- Hu B-Y, et al. (2010) Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci USA 107(9):4335-4340.
- Osafune K, et al. (2008) Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol 26(3):313-315.
- Bock C, et al. (2011) Reference Maps of human ES and iPS cell variation enable high- throughput characterization of pluripotent cell lines. Cell 144(3):439-452.
- Chetty S, et al. (2013) A simple tool to improve pluripotent stem cell differentiation. Nat Methods 10(6):553-556.
- Nostro MC, et al. (2011) Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138(5):861-871.
- Ginis I, et al. (2004) Differences between human and mouse embryonic stem cells. Dev Biol 269(2):360-380.
- Riedel MJ, et al. (2012) Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetologia 55(2):372-381.
- Polak M, Bouchareb-Banaei L, Scharfmann R, Czernichow P (2000) Early pattern of differentiation in the human pancreas. Diabetes 49(2):225-232.
- De Krijger RR, et al. (1992) The midgestational human fetal pancreas contains cells coex- pressing islet hormones. Dev Biol 153(2):368-375.
- Hayek A, Beattie GM (1997) Experimental transplantation of human fetal and adult pancreatic islets. J Clin Endocrinol Metab 82(8):2471-2475.
- Beattie GM, Butler C, Hayek A (1994) Morphology and function of cultured human fetal pancreatic cells transplanted into athymic mice: A longitudinal study. Cell Transplant 3(5):421-425.
- Rezania A, et al. (2012) Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61(8):2016-2029.
- Maehr R, et al. (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 106(37):15768-15773.
- Chen S, et al. (2009) A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol 5(4):258-265.
- Kelly OG, et al. (2011) Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 29(8):750-756.
- D'Amour KA, et al. (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24(11):1392-1401.
- Basford CL, et al. (2012) The functional and molecular characterisation of human em- bryonic stem cell-derived insulin-positive cells compared with adult pancreatic beta cells. Diabetologia 55(2):358-371.
- Micallef SJ, et al. (2012) INS(GFP/w) human embryonic stem cells facilitate isolation of in vitro derived insulin-producing cells. Diabetologia 55(3):694-706.
- Jiang J, et al. (2007) Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25(8):1940-1953.
- Tateishi K, et al. (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283(46):31601-31607.
- Zhang D, et al. (2009) Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 19(4):429-438.
- Xie R, et al. (2013) Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 12(2):224-237.
- Morán I, et al. (2012) Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab 16(4):435-448.
- Dorrell C, et al. (2011) Transcriptomes of the major human pancreatic cell types. Di- abetologia 54(11):2832-2844.
- Hrvatin S, Deng F, O'Donnell CW, Gifford DK, Melton DA (2014) MARIS: Method for analyzing RNA following intracellular sorting. PLoS ONE, 10.1371/journal.pone.0089459. · DOI
- Bonal C, Herrera PL (2008) Genes controlling pancreas ontogeny. Int J Dev Biol 52(7): 823-835.
- Blum B, et al. (2012) Functional beta-cell maturation is marked by an increased glu- cose threshold and by expression of urocortin 3. Nat Biotechnol 30(3):261-264.
- Bonett RM, Hu F, Bagamasbad P, Denver RJ (2009) Stressor and glucocorticoid- dependent induction of the immediate early gene kruppel-like factor 9: Implications for neural development and plasticity. Endocrinology 150(4):1757-1765.
- Lavado A, Lagutin OV, Chow LM, Baker SJ, Oliver G (2010) Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis. PLoS Biol 8(8):e1000460.
- Paz H, Lynch MR, Bogue CW, Gasson JC (2010) The homeobox gene Hhex regulates the earliest stages of definitive hematopoiesis. Blood 116(8):1254-1262.
- Steele-Perkins G, et al. (2005) The transcription factor gene Nfib is essential for both lung maturation and brain development. Mol Cell Biol 25(2):685-698.
- Weinhaus AJ, et al. (2003) Insulin secretagogues, but not glucose, stimulate an increase in [Ca2+]i in the fetal human and porcine beta-cell. J Clin Endocrinol Metab 88(6):2753-2759.
- Dalgin G, et al. (2011) Zebrafish mnx1 controls cell fate choice in the developing endocrine pancreas. Development 138(21):4597-4608.
- Sander M, et al. (2000) Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development 127(24):5533-5540.
- Yang Y-P, Thorel F, Boyer DF, Herrera PL, Wright CV (2011) Context-specific α-to-β-cell reprogramming by forced Pdx1 expression. Genes Dev 25(16):1680-1685.
- Collombat P, et al. (2003) Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 17(20):2591-2603.
- Petri A, et al. (2006) The effect of neurogenin3 deficiency on pancreatic gene ex- pression in embryonic mice. J Mol Endocrinol 37(2):301-316.
- Shih DQ, Navas MA, Kuwajima S, Duncan SA, Stoffel M (1999) Impaired glucose ho- meostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. Proc Natl Acad Sci USA 96(18):10152-10157.
- Aguayo-Mazzucato C, et al. (2011) Mafa expression enhances glucose-responsive in- sulin secretion in neonatal rat beta cells. Diabetologia 54(3):583-593.
- Brun T, et al. (2004) The diabetes-linked transcription factor PAX4 promotes beta-cell proliferation and survival in rat and human islets. J Cell Biol 167(6):1123-1135.
- Obermüller S, et al. (2010) Defective secretion of islet hormones in chromogranin-B deficient mice. PLoS ONE 5(1):e8936.
- Ingelsson E, et al.; MAGIC investigators (2010) Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes 59(5):1266-1275.
- Cheng X, et al. (2012) Self-renewing endodermal progenitor lines generated from human pluripotent stem cells. Cell Stem Cell 10(4):371-384.
- Harrow J, et al. (2012) GENCODE: The reference human genome annotation for The ENCODE Project. Genome Res 22(9):1760-1774.
- Trapnell C, et al. (2012) Differential gene and transcript expression analysis of RNA- seq experiments with TopHat and Cufflinks. Nat Protoc 7(3):562-578.
- Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11(10):R106.
Cited by
Sorted by citations
Generation of Functional Human Pancreatic β Cells In Vitro
Pagliuca, F. W., Millman, J. R., Gürtler, M., Segel, M., Van Dervort, A., Ryu, J. H., Peterson, Q. P., Greiner, D., & Melton, D. A. (2014) · Cell · doi:10.1016/j.cell.2014.09.040 · Cited by 2,025 · see citing works
“We use the nomenclature PH (polyhormonal, Figure 1A) to refer to this cell population of in-vitro-differentiated hPSCs. Transcriptional analysis of in-vitro-differentiated PH cells showed that these cells resemble human fetal and not adult b cells (Hrvatin et al., 2014).”
BackgroundMethodInfluentialSelf-citationThe Journal of Clinical Investigation
Witkin, E. M. (2016) · Journal of the American Dietetic Association · doi:10.1016/0002-8223(94)92394-9 · Cited by 920 · see citing works
In vitro generation of human pluripotent stem cell derived lung organoids
Dye, B. R., Hill, D. R., Ferguson, M. A. H., Tsai, Y.-H., Nagy, M. S., Dyal, R., Wells, J. M., Mayhew, C. N., Nattiv, R., Klein, O. D., et al. (2015) · eLife · doi:10.7554/elife.05098 · Cited by 824 · see citing works
“DOI: 10.7554/eLife.05098 16 of 25 (Si-Tayeb et al., 2009; Hrvatin et al., 2014).”
InfluentialCharting cellular identity during human in vitro β-cell differentiation
Veres, A., Faust, A. L., Bushnell, H. L., Engquist, E. N., Kenty, J. H.-R., Harb, G., Poh, Y.-C., Sintov, E., Gürtler, M., Pagliuca, F. W., et al. (2019) · Nature · doi:10.1038/s41586-019-1168-5 · Cited by 552 · see citing works
Self-citationInduced Pluripotent Stem Cells Meet Genome Editing
Hockemeyer, D., & Jaenisch, R. (2016) · Cell Stem Cell · doi:10.1016/j.stem.2016.04.013 · Cited by 499 · see citing works
“For one, it became evident that many protocols that were developed for the differentiation of hPSCs into functional tissue resulted in embryonic rather than adult human cell types (Bedada et al., 2015; Forster et al., 2014; Hrvatin et al., 2014; Spence et al., 2011; Takebe et al., 2013).”
BackgroundNair, G. G., Liu, J. S., Russ, H. A., Tran, S., Saxton, M. S., Chen, R., Juang, C., Li, M.-L., Nguyen, V. Q., Giacometti, S., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0271-4 · Cited by 472 · see citing works
Balboa, D., Barsby, T., Lithovius, V., Saarimäki-Vire, J., Omar-Hmeadi, M., Dyachok, O., Montaser, H., Lund, P.-E., Yang, M., Ibrahim, H., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01219-z · Cited by 433 · see citing works
Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells
Velazco-Cruz, L., Song, J., Maxwell, K. G., Goedegebuure, M. M., Augsornworawat, P., Hogrebe, N. J., & Millman, J. R. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.12.012 · Cited by 399 · see citing works
“These polyhormonal cells are known to not to resemble adult b cells and are not functional (D’Amour et al., 2006; Hrvatin et al., 2014).”
BackgroundSelf-citationGeneration of stem cell-derived β-cells from patients with type 1 diabetes
Millman, J., Xie, C.-H., VanDervort, A. V., Gürtler, M., Pagliuca, F., & Melton, D. (2016) · Nature Communications · doi:10.1038/ncomms11463 · Cited by 375 · see citing works
Self-citationImmune-evasive human islet-like organoids ameliorate diabetes
Yoshihara, E., O’Connor, C., Gasser, E., Wei, Z., Oh, T. G., Tseng, T. W., Wang, D., Cayabyab, F., Dai, Y., Yu, R. T., et al. (2020) · Nature · doi:10.1038/s41586-020-2631-z · Cited by 333 · see citing works
Boer, M., Stevens, G. W. J. M., Finkenauer, C., de Looze, M. E., & van den Eijnden, R. J. J. M. (2021) · Computers in Human Behavior · doi:10.1016/j.chb.2020.106645 · Cited by 335 · see citing works
Blodgett, D. M., Nowosielska, A., Afik, S., Pechhold, S., Cura, A. J., Kennedy, N. J., Kim, S., Kucukural, A., Davis, R. J., Kent, S. C., et al. (2015) · Diabetes · doi:10.2337/db15-0039 · Cited by 330 · see citing works
“Transcriptomes for each isolated cell can now be assessed with high fidelity and sensitivity, as recently described for pancreatic progenitors and b-cells (11,12).”
BackgroundMethodSelf-citationJennings, R. E., Berry, A. A., Strutt, J., Gerrard, D. T., & Hanley, N. (2015) · Development · doi:10.1242/dev.120063 · Cited by 301 · see citing works
“Indeed, Melton and colleagues identified transcriptional similarities between PSC-derived β-cells and human fetal β-cells, which may explain a relative lack of glucose responsiveness (Hrvatin et al., 2014).”
BackgroundAgulnick, A. D., Ambruzs, D. M., Moorman, M. A., Bhoumik, A., Cesario, R. M., Payne, J. K., Kelly, J. R., Haakmeester, C., Srijemac, R., Wilson, A. Z., et al. (2015) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0079 · Cited by 248 · see citing works
Finkbeiner, S. R., Hill, D. R., Altheim, C. H., Dedhia, P. H., Taylor, M. J., Tsai, Y.-H., Chin, A. M., Mahé, M. M., Watson, C. L., Freeman, J. J., et al. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.04.010 · Cited by 250 · see citing works
“This conclusion was in contrast to findings in other hPSC-derived lineages, such as pancreatic b-like cells and in lung organoids, which were shown to be more similar to fetal rather than adult tissue (Dye et al., 2015; Hrvatin et al., 2014).”
ResultOrganoid Models of Human Gastrointestinal Development and Disease
Dedhia, P. H., Bertaux‐Skeirik, N., Zavros, Y. L., & Spence, J. R. (2016) · Gastroenterology · doi:10.1053/j.gastro.2015.12.042 · Cited by 246 · see citing works
Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes
Hogrebe, N. J., Ishahak, M., & Millman, J. R. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.04.002 · Cited by 210 · see citing works
Self-citationAugsornworawat, P., Maxwell, K. G., Velazco-Cruz, L., & Millman, J. R. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108067 · Cited by 200 · see citing works
“Though categorized as maturation genes, the expression pattern ofMAFB trends similar to primary human b cells (Hrvatin et al., 2014; Veres et al., 2019).”
BackgroundInfluentialSelf-citationMulti-omic rejuvenation of human cells by maturation phase transient reprogramming
Gill, D., Parry, A., Santos, F., Okkenhaug, H., Todd, C. D., Hernando-Herraez, I., Stubbs, T. M., Milagre, I., & Reik, W. (2022) · eLife · doi:10.7554/elife.71624 · Cited by 185 · see citing works
“This is a valid concern as fully reprogrammed iPSCs can be difficult to differentiate into mature adult cells and instead these differentiated cells often resemble their foetal counterparts (Hrvatin et al., 2014).”
BackgroundBiomanufacturing for clinically advanced cell therapies
Aijaz, A., Li, M., Smith, D. W., Khong, D., LeBlon, C. E., Fenton, O. S., Olabisi, R. M., Libutti, S. K., Tischfield, J. A., Maus, M. V., et al. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0246-6 · Cited by 194 · see citing works
ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs
Hicks, M. R., Hiserodt, J., Paras, K. I., Fujiwara, W., Eskin, A., Jan, M., Xi, H., Young, C. S., Evseenko, D. A., Nelson, S. F., et al. (2017) · Nature Cell Biology · doi:10.1038/s41556-017-0010-2 · Cited by 194 · see citing works
Yoshihara, E., Wei, Z., Lin, C.-S., Fang, S., Ahmadian, M., Kida, Y. S., Tseng, T. W., Dai, Y., Yu, R. T., Liddle, C., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.03.005 · Cited by 165 · see citing works
Dynamic Pluripotent Stem Cell States and Their Applications
Wu, J., & Belmonte, J. C. I. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.10.009 · Cited by 163 · see citing works
“Despite the enormous potential that has been unleashed by pluripotent hESCs and hiPSCs, current in vitro strategies for differentiation to obtain functional and mature cell types for transplantation have been met with several major limitations: (1) only limited immature cell types of fetal or neonatal origin can be pr…”
Loomans, C. J. M., Giuliani, N. W., Balak, J. R. A., Ringnalda, F. C. A., van Gurp, L., Huch, M., Boj, S., Sato, T., Kester, L., Lopes, S. M. C. D. S., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.02.005 · Cited by 145 · see citing works
“While the phenotype of these cells has long been characterized by immature maturation (Hrvatin et al., 2014), recently more glucose-responsive cells have been generated from human pluripotent stem cells in vitro (Pagliuca et al., 2014; Rezania et al., 2014), but safety remains a major concern for…”
Patient-derived induced pluripotent stem cells in cancer research and precision oncology
Papapetrou, E. P. (2016) · Nature Medicine · doi:10.1038/nm.4238 · Cited by 159 · see citing works
Engineering islets from stem cells for advanced therapies of diabetes
Siehler, J., Blöchinger, A. K., Meier, M., & Lickert, H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00262-w · Cited by 125 · see citing works
Saxena, P., Heng, B.-O. C., Bai, P., Folcher, M., Zulewski, H., & Fussenegger, M. (2016) · Nature Communications · doi:10.1038/ncomms11247 · Cited by 124 · see citing works
KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas
Roost, M. S., van Iperen, L., Ariyürek, Y., Buermans, H. P. J., Arindrarto, W., Devalla, H. D., Passier, R. C., Mummery, C. L., Carlotti, F., de Koning, E. J. P., et al. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.05.002 · Cited by 128 · see citing works
“[13] hrvatin s, o’Donnell CW, Deng F, Millman jR, Pagliuca FW, Diiorio P, Rezania a, Gifford Dk, Melton Da: Differentiated human stem cells resemble fetal, not adult, beta cells.”
BackgroundInsights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics
Krentz, N. A. J., & Gloyn, A. L. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0325-0 · Cited by 128 · see citing works
Applications of iPSC-derived beta cells from patients with diabetes
Maxwell, K. G., & Millman, J. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100238 · Cited by 118 · see citing works
“Krentz et al.54 and Hrvatin et al.51 compared progenitor cell types to human islets.”
BackgroundSelf-citationTherapies for Type 1 Diabetes: Current Scenario and Future Perspectives
Pathak, V., Pathak, N., O'Neill, C., Guduric-Fuchs, J., & Medina, R. (2019) · Clinical Medicine Insights: Endocrinology and Diabetes · doi:10.1177/1179551419844521 · Cited by 116 · see citing works
A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion
Helman, A., Cangelosi, A. L., Davis, J. C., Pham, Q., Rothman, A., Faust, A. L., Straubhaar, J., Sabatini, D. M., & Melton, D. A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.04.004 · Cited by 129 · see citing works
“In recent years, a more advanced understanding of the intrinsic transcriptional programs in vivo led to a rapid progress in the generation of many cell types, including b cells, from human pluripotent stem cells (Hrvatin et al., 2014; Sneddon et al., 2018).”
BackgroundSelf-citationReversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway
Blum, B., Roose, A. N., Barrandon, O., Maehr, R., Arvanites, A. C., Davidow, L. S., Davis, J. C., Peterson, Q. P., Rubin, L. L., & Melton, D. A. (2014) · eLife · doi:10.7554/elife.02809 · Cited by 133 · see citing works
“…et al., 2014), and despite evidence that UCN3 is not a faithful marker for functional β cell maturation in human islets during human pancreas development (Hrvatin et al., 2014), the signals that reverse β cell de-differentiation (i.e., inhibition of Alk5 signaling) may be conserved between mouse…”
BackgroundSelf-citationNair, G. G., & Hebrok, M. (2015) · Current Opinion in Genetics and Development · doi:10.1016/j.gde.2015.03.004 · Cited by 108 · see citing works
Editing the genome of hiPSC with CRISPR/Cas9: disease models
Bassett, A. R. (2017) · Mammalian Genome · doi:10.1007/s00335-017-9684-9 · Cited by 110 · see citing works
“In the context of disease modelling, such sequences are much more poorly conserved between organisms than protein coding sequences, often making it impossible to identify the orthologous region in other species.”
BackgroundGeneration of pancreatic β cells for treatment of diabetes: advances and challenges
Shahjalal, H., Dayem, A. A., Lim, K., Jeon, T.-I., & Cho, S.-G. (2018) · Stem cell research & therapeutics · doi:10.1186/s13287-018-1099-3 · Cited by 101 · see citing works
“The polyhormonal cells may resemble the immature β cells observed in mid-gestation human fetal pancreases [70, 71].”
BackgroundThe promise of stem cell-derived islet replacement therapy
Melton, D. (2021) · Diabetologia · doi:10.1007/s00125-020-05367-2 · Cited by 96 · see citing works
Self-citationAutologous Pluripotent Stem Cell–Derived β-Like Cells for Diabetes Cellular Therapy
Millman, J., & Pagliuca, F. (2017) · Diabetes · doi:10.2337/db16-1406 · Cited by 97 · see citing works
Self-citationStem Cells: A Renaissance in Human Biology Research
Wu, J., & Belmonte, J. C. I. (2016) · Cell · doi:10.1016/j.cell.2016.05.043 · Cited by 107 · see citing works
“…cell types that can potentially interfere with the interpretation of downstream assays; (2) hPSC differentiation mostly generates fetal cell types (Hrvatin et al., 2014; van den Berg et al., 2015), which also seems to be the case for hPSC-derived organoids (Dye et al., 2015; Finkbeiner et al.,…”
BackgroundBiologically inspired approaches to enhance human organoid complexity
Holloway, E. M., Capeling, M. M., & Spence, J. R. (2019) · Development · doi:10.1242/dev.166173 · Cited by 96 · see citing works
“In addition, regardless of culture duration, pluripotent stem cell-derived organoids fail to mature in vitro, and remain similar to fetal tissue (Aurora and Spence, 2016; Camp et al., 2015; Chen et al., 2017; Finkbeiner et al., 2015b; Hrvatin et al., 2014; Takasato et al., 2015).”
BackgroundKim, Y., Kim, H., Ko, U., Oh, Y., Lim, A., Sohn, J.-W., Shin, J., Kim, H., & Han, Y.-M. (2016) · Scientific Reports · doi:10.1038/srep35145 · Cited by 90 · see citing works
Modelling the endocrine pancreas in health and disease
Bakhti, M., Böttcher, A., & Lickert, H. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0132-z · Cited by 96 · see citing works
Cell Maturation: Hallmarks, Triggers, and Manipulation
Alvarez-Dominguez, J., & Melton, D. (2021) · Cell · doi:10.1016/j.cell.2021.12.012 · Cited by 78 · see citing works
Self-citationiPSC technology‐based regenerative therapy for diabetes
Kondo, Y., Toyoda, T., Inagaki, N., & Osafune, K. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12702 · Cited by 81 · see citing works
Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors
Memon, B., & Abdelalim, E. M. (2020) · Cells · doi:10.3390/cells9020283 · Cited by 75 · see citing works
“Therefore, their use as an encapsulant for hPSC‐derived beta cells, without a protective retrievable device could raise concerns as hPSC‐derived beta cells have not yet been proven to be completely identical to pancreatic adult islets [27] and require their retrieval periodically to assess their viability, function, a…”
BackgroundMemon, B., Karam, M., Al‐Khawaga, S., & Abdelalim, E. M. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-017-0759-z · Cited by 84 · see citing works
Dye, B. R., Youngblood, R. L., Oakes, R. S., Kasputis, T., Clough, D. W., Spence, J. R., & Shea, L. D. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.119757 · Cited by 75 · see citing works
Augsornworawat, P., Hogrebe, N. J., Ishahak, M., Schmidt, M. D., Marquez, E., Maestas, M. M., Veronese-Paniagua, D., Gale, S. E., Miller, J. R., Velazco-Cruz, L., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01150-8 · Cited by 85 · see citing works
Self-citationSilva, I. B. B., Kimura, C. H., Colantoni, V. P., & Sogayar, M. (2022) · Stem cell research & therapeutics · doi:10.1186/s13287-022-02977-y · Cited by 68 · see citing works
All mixed up: defining roles for β-cell subtypes in mature isletsPreprint
Liu, J. S. E., & Hebrok, M. (2017) · Genes & Development · doi:10.1101/gad.294389.116 · Cited by 68 · see citing works
“…knockdown of the same miRNAs could improve function in immature islets suggests that these miRNAs either are only unidirectionally effective at a specific stage in the transition from immature to mature cells or become redundant when other maturation landmarks are in place (Jacovetti et al. 2015).”
BackgroundInfluentialReport from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement
Bartlett, S. T., Markmann, J. F., Johnson, P., Korsgren, O., Hering, B. J., Scharp, D. W., Kay, T. W. H., Bromberg, J. S., Odorico, J. S., Weir, G. C., et al. (2016) · Transplantation · doi:10.1097/tp.0000000000001055 · Cited by 74 · see citing works
“The PluriTest assay may prove to be valuable for this purpose.(306,307) Ultimately, a fully terminally differentiated purified cell population may have an extremely low teratoma risk profile, but determining this preclinically for a given cell population would have merit.”
MethodInduced pluripotent stem cells as a model for diabetes investigation
Stępniewski, J., Kachamakova‐Trojanowska, N., Ogrocki, D., Szopa, M., Matłok, M., Beilharz, M., Dyduch, G., Malecki, M. T., Józkowicz, A., & Dulak, J. (2015) · Scientific Reports · doi:10.1038/srep08597 · Cited by 67 · see citing works
Weng, C., Xi, J., Li, H., Cui, J., Gu, A., Lai, S., Leskov, K., Ke, L., Jin, F., & Li, Y. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00314-2 · Cited by 65 · see citing works
“Synapse part (610) Regulation of secretion (699) Pancreatic beta cells (40) Neurotransmitter transport (155) Cell–cell signalling (767) Regulation of calcium ion transport into cytosol (92) Cellular response to fatty acid (51) Sodium channel regulator activity (32) Regulation of sodium transporter activity (38) Cation…”
hPSC-derived lung and intestinal organoids as models of human fetal tissue
Aurora, M., & Spence, J. R. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.06.006 · Cited by 69 · see citing works
Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?
Bourgeois, S., Sawatani, T., Mulders, A. V., Leu, N. D., Heremans, Y., Heimberg, H., Cnop, M., & Staels, W. (2021) · Cells · doi:10.3390/cells10010191 · Cited by 61 · see citing works
Dye, B. R., Youngblood, R., Oakes, R., Kasputis, T., Clough, D. W., Nagy, M. S., Spence, J., & Shea, L. (2019) · bioRxiv · doi:10.1101/564252 · Cited by 58
LIM domain–binding 1 maintains the terminally differentiated state of pancreatic &bgr; cells
Ediger, B. N., Lim, H., Juliana, C., Groff, D., Williams, L. T., Dominguez, G., Liu, J.-H., Taylor, B., Walp, E., Kameswaran, V., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88016 · Cited by 55 · see citing works
Ng, N. H. J., Jasmen, J. B., Lim, C. S., Lau, H. H., Krishnan, V. G., Kadiwala, J., Kulkarni, R. N., Ræder, H., Vallier, L., Hoon, S., et al. (2019) · iScience · doi:10.1016/j.isci.2019.05.032 · Cited by 54 · see citing works
“On the contrary, currently available pancreatic b cell differentiation protocols are often unable to generate functional 202 iScience 16, 192–205, June 28, 2019 b cells in vitro and require transplantation into mice for in vivo maturation (Hrvatin et al., 2014; Loo et al., 2018).”
BackgroundThe Importance of Proper Oxygenation in 3D Culture
Tse, H., Gardner, G., Domínguez-Bendala, J., & Fraker, C. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.634403 · Cited by 54 · see citing works
Ramond, C., Glaser, N., Berthault, C., Ameri, J., Kirkegaard, J. S., Hansson, M., Honoré, C., Semb, H., & Scharfmann, R. (2017) · eLife · doi:10.7554/elife.27564 · Cited by 54 · see citing works
“This is the case for hepatocytes (Baxter et al., 2015), cardiomyocytes (Karakikes et al., 2015), neurons (Playne and Connor, 2017) and pancreatic beta cells (Hrvatin et al., 2014).”
BackgroundJohnson, J. D. (2016) · Diabetologia · doi:10.1007/s00125-016-4059-4 · Cited by 54 · see citing works
Oshima, M., Pechberty, S., Bellini, L., Göpel, S., Campana, M., Rouch, C., Dairou, J., Cosentino, C., Fantuzzi, F., Toivonen, S., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-05046-x · Cited by 53 · see citing works
Pancreatic Islet Cell Development and Regeneration
Romer, A. I., & Sussel, L. (2015) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000174 · Cited by 53 · see citing works
Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition
Castro-Gutiérrez, R., Alkanani, A. K., Mathews, C. E., Michels, A. W., & Russ, H. A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.707881 · Cited by 60 · see citing works
“It is intriguing to speculate that sBC, which have been proposed to closer resemble fetal rather than adult beta cells (31), might display an immature immune profile when challenged.”
BackgroundIslet organoid as a promising model for diabetes
Zhang, X., Ma, Z., Song, E., & Xu, T. (2021) · Protein & Cell · doi:10.1007/s13238-021-00831-0 · Cited by 52 · see citing works
“However, in these previous studies, the immaturity of sc-β cells, as demonstrated by the poor glucose responsiveness, polyhormonal signatures, and preferential commitment of the polyhormonal cells to α instead of β cells, has been reported (Kelly et al., 2011; Basford et al., 2012; Rezania et al., 2013; Bruin et al.,…”
BackgroundResultShaping Pancreatic β-Cell Differentiation and Functioning: The Influence of Mechanotransduction
Galli, A., Marku, A., Marciani, P., Schulte, C., Lenardi, C., Paolo, M., Maffioli, E., Tedeschi, G., & Perego, C. (2020) · Cells · doi:10.3390/cells9020413 · Cited by 49 · see citing works
Beamish, C. A., Strutt, B., Arany, E., & Hill, D. (2016) · Islets · doi:10.1080/19382014.2016.1162367 · Cited by 49 · see citing works
A Stem Cell Approach to Cure Type 1 Diabetes.Preprint
Helman, A., & Melton, D. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035741 · Cited by 48 · see citing works
Self-citationConcise Review: Human Pluripotent Stem Cells for the Modeling of Pancreatic β‐Cell Pathology
Balboa, D., Saarimäki-Vire, J., & Otonkoski, T. (2018) · Stem Cells · doi:10.1002/stem.2913 · Cited by 48 · see citing works
Aguayo-Mazzucato, C., DiIenno, A. R., Hollister-Lock, J., Cahill, C., Sharma, A. J., Weir, G., Colton, C., & Bonner-Weir, S. (2015) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2015-2632 · Cited by 47 · see citing works
Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells.
Abdelalim, E. M., & Emara, M. (2015) · World Journal of Stem Cells · doi:10.4252/wjsc.v7.i1.174 · Cited by 47 · see citing works
ENTPD3 Marks Mature Stem Cell–Derived β-Cells Formed by Self-Aggregation In Vitro
Docherty, F. M., Riemondy, K. A., Castro-Gutiérrez, R., Dwulet, J. M., Shilleh, A. H., Hansen, M. S., Williams, S. P. M., Armitage, L. H., Santostefano, K. E., Wallet, M. A., et al. (2021) · Diabetes · doi:10.2337/db20-0873 · Cited by 69 · see citing works
“Furthermore, we confirm the existence of previously described fetal-like sBC and sBC with cohormone transcript expression (37) and a small subpopulation of proliferating sBC (38).”
BackgroundMutations and variants of ONECUT1 in diabetes
Philippi, A., Heller, S., Costa, I. G., Senée, V., Breunig, M., Li, Z., Kwon, G., Russell, R., Illing, A., Lin, Q., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01502-7 · Cited by 55 · see citing works
Higuchi, A., Kumar, S., Ling, Q.-D., Alarfaj, A., Munusamy, M. A., Murugan, K., Hsu, S.-T., Benelli, G., & Umezawa, A. (2017) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2016.09.002 · Cited by 44 · see citing works
Chmielowiec, J., Szlachcic, W. J., Yang, D., Scavuzzo, M. A., Wamble, K., Sarrion-Perdigones, A., Sabek, O., Venken, K., & Borowiak, M. (2022) · Nature Communications · doi:10.1038/s41467-022-29646-1 · Cited by 43 · see citing works
(Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives
Baeyens, L., Lemper, M., Staels, W., Groef, S. D., Leu, N. D., Heremans, Y., German, M. S., & Heimberg, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2016 · Cited by 50 · see citing works
Kassem, D., Kamal, M. M., El-Kholy, A., & El-Mesallamy, H. (2016) · Stem cell research & therapeutics · doi:10.1186/s13287-016-0374-4 · Cited by 43 · see citing works
“Nevertheless, despite all of the vigorous efforts to generate mature functioning β cells from MSCs or even other types of stem cells, the majority of the obtained IPCs mostly fail to properly secrete insulin in response to glucose, and the reason for such anomalies together with the mechanisms through which differenti…”
BackgroundBlanchi, B., Taurand, M., Colace, C., Thomaidou, S., Audeoud, C., Fantuzzi, F., Sawatani, T., Gheibi, S., Sabadell-Basallote, J., Boot, F., et al. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101772 · Cited by 42 · see citing works
“We next focused on 54 transcripts encoding proteins important for beta cell function (Figure 2D) [5,14,15].”
Characterization of stem-cell-derived islets during differentiation and after implantation
Cuesta-Gomez, N., Verhoeff, K., Jasra, I. T., Pawlick, R., Dadheech, N., & Shapiro, A. M. J. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111238 · Cited by 41 · see citing works
Coronnello, C., & Francipane, M. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10302-y · Cited by 41 · see citing works
“In many cases, the progeny of iPSCs are comparable to an immature fetal stage [9–11].”
BackgroundMolecular and genetic regulation of pig pancreatic islet cell development
Kim, S., Whitener, R. L., Peiris, H. S., Gu, X., Chang, C., Lam, J. Y., Camuñas-Soler, J., Park, I., Bevacqua, R. J., Tellez, K., et al. (2020) · Development · doi:10.1242/dev.186213 · Cited by 41 · see citing works
“Transcriptome analysis described here provides evidence of genetic regulatory mechanisms and cell development in pigs that are also conserved in other mammals, including (1) cell typespecific expression of transcription factors (PDX1, MAFA, ARX, IRX, HHEX) and functional regulators (PCSK1, PCSK2, SLC2A2, SLC30A8, GLP1…”
BackgroundDye, B. R., Miller, A. J., & Spence, J. R. (2016) · Current Pathobiology Reports · doi:10.1007/s40139-016-0102-x · Cited by 46 · see citing works
Pancreatic Stem Cells Remain Unresolved
Jiang, F., & Morahan, G. (2014) · Stem Cells and Development · doi:10.1089/scd.2014.0214 · Cited by 39 · see citing works
The Vascularised Chamber as an In Vivo Bioreactor.
Yap, K., Yeoh, G., Morrison, W., & Mitchell, G. (2018) · Trends in Biotechnology · doi:10.1016/j.tibtech.2018.05.009 · Cited by 39 · see citing works
Human Pluripotent Stem Cells to Model Islet Defects in Diabetes
Balboa, D., Iworima, D. G., & Kieffer, T. J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.642152 · Cited by 47 · see citing works
Khatib, M. E. E., Ohmine, S., Jacobus, E. J., Tonne, J. M., Morsy, S. G., Holditch, S., Schreiber, C. A., Uetsuka, K., Fusaki, N., Wigle, D., et al. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0017 · Cited by 38 · see citing works
Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes
Tahbaz, M., & Yoshihara, E. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.716625 · Cited by 42 · see citing works
Modeling rare diseases with induced pluripotent stem cell technology
Anderson, R. H., & Francis, K. R. (2018) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2018.01.001 · Cited by 43 · see citing works
Pancreas-on-a-Chip Technology for Transplantation Applications
Abadpour, S., Aizenshtadt, A., Olsen, P. A., Shoji, K., Wilson, S., Krauss, S., & Scholz, H. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01357-1 · Cited by 36 · see citing works
hPSC-derived organoids: models of human development and disease
Frum, T., & Spence, J. R. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01969-w · Cited by 40 · see citing works
Pan, G., Mu, Y., Hou, L., & Liu, J.-P. (2018) · Annales d'Endocrinologie · doi:10.1016/j.ando.2018.06.1084 · Cited by 36 · see citing works
From Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes
Mattis, K. K., & Gloyn, A. L. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.045 · Cited by 39 · see citing works
Pezzolla, D., López-Beas, J., Lachaud, C., Dominguez-Rodriguez, A., Smani, T., Hmadcha, A., & Soria, B. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119904 · Cited by 34 · see citing works
Recent advances in cell replacement therapies for the treatment of type 1 diabetes.
Cogger, K. F., & Nostro, M. (2015) · Endocrinology · doi:10.1210/en.2014-1691 · Cited by 34 · see citing works
Human stem cell-based disease modeling: prospects and challenges
Johnson, J. Z., & Hockemeyer, D. F. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2015.10.007 · Cited by 32 · see citing works
Stem cells to restore insulin production and cure diabetes
Sordi, V., Pellegrini, S., Krampera, M., Marchetti, P., Pessina, A., Ciardelli, G., Fadini, G. P., Pintus, C., Pantè, G., & Piemonti, L. (2017) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2017.02.004 · Cited by 30 · see citing works
Kumar, S., Alarfaj, A., Munusamy, M. A., Singh, A. K., Peng, I.-C., Priya, S., Hamat, R., & Higuchi, A. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151223418 · Cited by 31 · see citing works
Andersson-Rolf, A., Groot, K., Korving, J., Begthel, H., Hanegraaf, M. A. J., VanInsberghe, M. A., Salmén, F., van den Brink, S., López‐Iglesias, C., Peters, P. J., et al. (2024) · Cell · doi:10.1016/j.cell.2024.10.044 · Cited by 35 · see citing works
Maturing differentiated human pluripotent stem cells in vitro: methods and challenges.
Ottaviani, D., ter Huurne, M., Elliott, D., Bellin, M., & Mummery, C. (2023) · Development · doi:10.1242/dev.201103 · Cited by 29 · see citing works
Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation
Heller, S., Li, Z., Lin, Q., Geusz, R. J., Breunig, M., Hohwieler, M., Zhang, X., Nair, G. G., Seufferlein, T. T. W., Hebrok, M., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02818-3 · Cited by 29 · see citing works
- Authors
- Hrvatin, S., O’Donnell, C. W., Deng, F., Millman, J. R., Pagliuca, F. W., DiIorio, P., Rezania, A., Gifford, D. K., & Melton, D. A.
- Affiliations
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute and
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Janssen Research & Development (United States) (US)
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-02-10
- Volume
- 111
- Issue
- 8
- Pages
- 3038-3043
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3939927
- OpenAlex
- W2055001415
- Cited by
- 302
- References
- 0
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 19 · 2023: 30 · 2022: 25 · 2021: 33 · 2020: 42 · 2019: 15 · 2018: 18 · 2017: 15 · 2016: 47 · 2015: 25 · 2014: 8
- FWCI
- 31.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (U01HL100408, 1U01HL10040804)
- National Institute of Diabetes and Digestive and Kidney Diseases (RL1DK081184, 2U01DK07247307, U01DK072473)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- human pluripotent stem cells, pancreatic beta cells, fetal pancreas, gene expression profiling, stem cell differentiation, beta cell maturation, islet transplantation, gene expression signatures
- MeSH terms
- Adult, Cell Differentiation, Fetus, Flow Cytometry, Humans, Pancreas, Gene Expression Profiling, Pluripotent Stem Cells, Microarray Analysis, 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 ›
Are you an author, or do you see a problem with this page? Request a review
