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Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo
Abstract
Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell-derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.
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“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”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [31]
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BackgroundIn 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 846
“In contrast, FOXA2, which is expressed in the foregut (Monaghan et al., 1993; Ang and Rossant, 1994; D’Amour et al., 2005, 2006; Kroon et al., 2008; Si-Tayeb et al., 2009; DeLaForest et al., 2011) and in some neural tissues (Stott et al., 2013), had high expression in ventral foregut spheroids, but…”
BackgroundUnlimited in vitro expansion of adult bi‐potent pancreas progenitors through the Lgr5/R‐spondin axis
Huch, M., Bonfanti, P., Boj, S. F., Sato, T., Loomans, C. J. M., van de Wetering, M., Sojoodi, M., Li, V. S. W., Schuijers, J., Gracanin, A., et al. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.204 · Cited by 726
“…iPSCs can be differentiated towards beta cells in vitro (D’Amour et al , 2006; Zhang et al , 2009; Nostro et al , 2011; Cheng et al , 2012) and in vivo (Soria et al , 2000; Kroon et al , 2008; Sneddon et al , 2012), but the reproducibility of such procedures has been limited (Lysy et al , 2012).”
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InfluentialPancreas organogenesis: From bud to plexus to gland
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BackgroundZhang, D., Jiang, W., Liu, M., Sui, X. Y., Yin, X., Chen, S., Shi, Y., & Deng, H. (2009) · Cell Research · doi:10.1038/cr.2009.28 · Cited by 588
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BackgroundResultInfluentialGeneration of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells.
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“display bona fide teratoma histology (Eshpeter et al. 2008; Kroon et al., 2008), similar to outgrowths described in our own previous work (Phillips et al.”
InfluentialIntroduction to Stem Cells and Regenerative Medicine
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“processed human insulin, and protecting against streptozotocin (STZ)-induced hyperglycemia in mice [6], [7].”
BackgroundMethodResultInfluentialSelf-citationPluripotent stem cells in regenerative medicine: challenges and recent progress
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“Another approach is to derive b cells from pluripotent cells (Kroon et al., 2008).”
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BackgroundInfluentialAcquisition of Dynamic Function in Human Stem Cell-Derived β Cells
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BackgroundKennedy, M., Awong, G., Sturgeon, C. M., Ditadi, A., LaMotte-Mohs, R., Zúñiga-Pflücker, J., & Keller, G. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.11.003 · Cited by 395
“…Wnt pathways all play a role in the early induction steps in hPSC cultures, including primitive streak formation, mesoderm induction, and hematopoietic specification (Davis et al., 2008; Jackson et al., 2010; Kennedy et al., 2007; Kroon et al., 2008; Sumi et al., 2008; Vijayaragavan et al., 2009).”
BackgroundGeneration of Insulin-secreting Islet-like Clusters from Human Skin Fibroblasts
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Generation of stem cell-derived β-cells from patients with type 1 diabetes
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Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant
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On the origin of the β cellPreprint
Oliver-Krasinski, J. M., & Stoffers, D. A. (2008) · Genes & Development · doi:10.1101/gad.1670808 · Cited by 361
“Although success in achieving stem cell differentiation into insulin expressing cells has been highly variable and even controversial, recent reports indicate highly promising results in the derivation of endodermlike cells from embryonic stem (ES) cells and subsequent in vitro or in vivo differentiation into insulin-…”
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Cardinale, V., Wang, Y., Carpino, G., Cui, C.-B., Gatto, M., Rossi, M., Berloco, P. B., Cantàfora, A., Wauthier, E., Furth, M. E., et al. (2010) · Hepatology · doi:10.1002/hep.24590 · Cited by 345
“Moreover, any therapy based on ES or iPS cells may be limited by the potential of teratoma formation, usually ascribed to residual undifferentiated stem cells.(28,29) Our findings that there are endodermal stem/progenitors in the biliary trees of all donor ages; that they clonogenically expand in vitro under wholly de…”
BackgroundKelly, O. G., Chan, M. Y., Martinson, L. A., Kadoya, K., Ostertag, T. M., Ross, K. G., Richardson, M., Carpenter, M. K., D'Amour, K. A., Kroon, E., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1931 · Cited by 348
“Previously, we demonstrated the directed differentiation of hES cells into pancreatic lineage”
BackgroundSelf-citationRamzy, 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., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.10.003 · Cited by 342
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Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity
Li, J., Casteels, T., Frogne, T., Ingvorsen, C., Honoré, C., Courtney, M. L., Huber, K., Schmitner, N., Kimmel, R. A., Romanov, R. A., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.010 · Cited by 397
“…stem cells (ESCs), induced pluripotent stem cells (iPSCs), hepatic cells, exocrine cells, and other endocrine cells (Al-Hasani et al., 2013; Chera et al., 2014; Collombat et al., 2009; Kroon et al., 2008; Pagliuca et al., 2014; Sangan et al., 2015; Talchai et al., 2012; Zhou et al., 2008).”
Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions
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“cells (42), motor neurons (43), oligodendrocyte progenitors (44, 45), pancreatic progenitors (4, 46), hepatocyte-like cells (47), retinal cells (48), and others (49, 50).”
BackgroundPancreas Organogenesis: From Lineage Determination to Morphogenesis
Shih, H.-P., Wang, A., & Sander, M. (2013) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101512-122405 · Cited by 347
“These in vitro–generated progenitors also pass the functional test of having the potential to form mature endocrine, ductal, and acinar cells when transplanted into mice (Kelly et al. 2011, Kroon et al. 2008, Rezania et al. 2012, Schulz et al. 2012, Xie et al. 2013).”
InfluentialRovira, M., Scott, S.-G., Liss, A. S., Jensen, J. N., Thayer, S. P., & Leach, S. D. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912589107 · Cited by 296
“Retinoids have previously been shown to exert profound influences on vertebrate pancreas development (29–31), and retinoic acid is a critical component for directed differentiation of human ES cells into insulin-producing β-cells (32).”
BackgroundFasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes
Cheng, C., Villani, V., Buono, R., Wei, M., Kumar, S., Yilmaz, Ö. H., Cohen, P., Sneddon, J. B., Perin, L., & Longo, V. D. (2017) · Cell · doi:10.1016/j.cell.2017.01.040 · Cited by 335
“, 2013), depletion of β cells and the consequent loss of insulin secretion during late stage diabetes have often been considered conditions whose reversals require islet and stem cells transplantation (Fiorina et al., 2008; Kroon et al., 2008; Milanesi et al., 2012; Pipeleers et al., 2002; Villani et al., 2014).”
Bioprinting: From Tissue and Organ Development to in Vitro Models
Mota, C., Camarero‐Espinosa, S., Baker, M. B., Wieringa, P. A., & Moroni, L. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.9b00789 · Cited by 359
Differentiated human stem cells resemble fetal, not adult, β cells
Hrvatin, S., O’Donnell, C. W., Deng, F., Millman, J. R., Pagliuca, F. W., DiIorio, P., Rezania, A., Gifford, D. K., & Melton, D. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1400709111 · Cited by 302
“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).”
BackgroundNostro, M., Sarangi, F., Yang, C.-X., Holland, A. M., Elefanty, A., Stanley, E., Greiner, D. L., & Keller, G. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.02.017 · Cited by 302
“Populations enriched in NKX6-1 cells will give rise to functional beta cells following transplantation into immunodeficient mice, indicating that they do indeed represent progenitors of adult monohormonal lineages (Kelly et al., 2011; Kroon et al., 2008).”
BackgroundResultInfluentialJennings, R. E., Berry, A. A., Strutt, J. P. B., Gerrard, D. T., & Hanley, N. A. (2015) · Development · doi:10.1242/dev.120063 · Cited by 357
“, 2001), there has been a convergence of differentiation protocols during the last decade around the pioneering publications of Baetge and colleagues (D’Amour et al., 2005, 2006; Kroon et al., 2008; reviewed by Docherty et al., 2007; Pagliuca and Melton, 2013).”
BackgroundGenetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation
Zaret, K. S. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2318 · Cited by 295
“Because, after ES-cell-differentiation protocols, only a fraction of cells show functional capacity after transplantation to mouse models, these terminal cells might not be properly programmed, or earlier stage cells in the population might be differentiating in situ”
BackgroundMulti-lineage human iPSC-derived platforms for disease modeling and drug discovery
Sharma, A., Sances, S., Workman, M. J., & Svendsen, C. N. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.02.011 · Cited by 296
“In particular, mice with inhibited immune systems are commonly used as recipients of human donor tissues to test the engraftment of hiPSC-derived cell types including muscle, neural tissues, and pancreatic cells (Funakoshi et al., 2016; Jeon et al., 2012; Kroon et al., 2008; Nori et al., 2011).”
BackgroundGATA6 haploinsufficiency causes pancreatic agenesis in humans
Allen, H., Flanagan, S., Shaw-Smith, C., Franco, E. D., Akerman, I., Caswell, R., Ferrer, J., Hattersley, A., & Ellard, S. (2011) · Nature Genetics · doi:10.1038/ng.1035 · Cited by 296
Introduction to diabetes mellitus.
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Artificial three-dimensional niches deconstruct pancreas development in vitro
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“Robust protocols to produce endoderm from embryonic stem cells or induced pluripotent stem cells are available and production of pancreatic progenitors after endoderm induction is becoming possible (Kroon et al., 2008; Ameri et al., 2010; Cheng et al., 2012).”
Chen, A. K.-L., Reuveny, S., & Oh, S. K. W. (2013) · Biotechnology Advances · doi:10.1016/j.biotechadv.2013.03.006 · Cited by 299
“The endodermal cell aggregates expressed various marker genes, such as HNF6, FOXA2 and PDX1 which indicated that they were of the pancreatic endoderm (Kroon et al., 2008).”
BackgroundDevelopment of the Human Pancreas From Foregut to Endocrine Commitment
Jennings, R. E., Berry, A. A., Kirkwood-Wilson, R., Roberts, N. A., Hearn, T., Salisbury, R. J., Blaylock, J., Hanley, K. P., & Hanley, N. (2013) · Diabetes · doi:10.2337/db12-1479 · Cited by 285
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Self-citationTurning straw into gold: directing cell fate for regenerative medicine
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“The earliest differentiation protocols focused on deriving insulin-producing b -like cells in vitro from embryonic stem cells (ESCs) 7–10 and iPSCs.”
Human Fetal Membranes: A Source of Stem Cells for Tissue Regeneration and Repair?
Ilancheran, S., Moodley, Y. P., & Manuelpillai, U. (2008) · Placenta · doi:10.1016/j.placenta.2008.09.009 · Cited by 276
The Promise and Perils of Stem Cell Therapeutics
Daley, G. Q. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.05.010 · Cited by 262
Rezania, A., Bruin, J. E., Xu, J., Narayan, K., Fox, J., O'Neil, J., & Kieffer, T. (2013) · Stem Cells · doi:10.1002/stem.1489 · Cited by 269
Mouse liver repopulation with hepatocytes generated from human fibroblasts
Zhu, S.-Y., Rezvani, M., Harbell, J., Mattis, A. N., Wolfe, A., Benet, L., Willenbring, H., & Ding, S. (2014) · Nature · doi:10.1038/nature13020 · Cited by 266
MafA and MafB Regulate Genes Critical to β-Cells in a Unique Temporal Manner
Artner, I., Hang, Y., Mazur, M., Yamamoto, T., Guo, M., Lindner, J., Magnuson, M., & Stein, R. (2010) · Diabetes · doi:10.2337/db10-0190 · Cited by 263
“The significance of these proteins was recently reinforced upon observing their expression during the stepwise differentiation of human embryonic stem cells to -like cells (4,5) and the reprogramming of adult acinar cells to -like cells upon misexpression of a unique subset of transcription factors, specifically MafA,…”
BackgroundZachos, N. C., Kovbasnjuk, O. N., Foulke-Abel, J. D., In, J., Blutt, S. E., de Jonge, H. R., Estes, M. K., & Donowitz, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.635995 · Cited by 308
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“Enhancers for Islet Cell Functional Genes Are Poised prior to Terminal Differentiation An important characteristic of hESC-derived PE is its competency to differentiate into functional endocrine cells after subcutaneous engraftment into mice (Kroon et al., 2008; Xie et al., 2013).”
BackgroundIdentification of small molecules for human hepatocyte expansion and iPS differentiation
Shan, J., Schwartz, R. E., Ross, N. T., Logan, D. J., Thomas, D., Duncan, S. A., North, T. E., Goessling, W., Carpenter, A. E., & Bhatia, S. N. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1270 · Cited by 254
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“83 These studies were fundamental in the establishment of a robust methodology for consistent, large scale production of this cellular source by Schulz et al 84 which will undoubtedly serve as a platform to circumvent cadaveric donor shortages by providing a potentially unlimited supply of…”
Alipio, Z., Liao, W., Roemer, E. J., Waner, M., Fink, L., Ward, D., & Ma, Y.-P. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1007884107 · Cited by 253
Targeting the pancreatic β-cell to treat diabetes
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Dynamic Signaling Network for the Specification of Embryonic Pancreas and Liver Progenitors
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Current status of pluripotent stem cells: moving the first therapies to the clinic
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Agulnick, 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
Self-citationSchaffer, A., Taylor, B., Benthuysen, J., Liu, J., Thorel, F., Yuan, W., Jiao, Y., Kaestner, K., Herrera, P., Magnuson, M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003274 · Cited by 246
“Given the simultaneous initiation of multiple endocrine subtype programs in one cell with current human embryonic stem cell (hESC) differentiation protocols [18,19], such knowledge is critical for refining these protocols to support the differentiation of mature and functional beta cells in vitro.”
BackgroundXie, R., Everett, L. J., Lim, H., Patel, N. A., Schug, J., KROON, E. J., Kelly, O., Wang, A., D’Amour, K. A., Robins, A. J., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.11.023 · Cited by 245
“As reported (D’Amour et al., 2006; Kroon et al., 2008), endocrine cells coexpressed multiple hormones (Figure 1H) and were mostly devoid of the b cell transcription factors (TFs) PDX1 and NKX6.”
BackgroundInfluentialSelf-citationThe Adult Mouse and Human Pancreas Contain Rare Multipotent Stem Cells that Express Insulin
Smukler, S. R., Arntfield, M. E., Razavi, R., Bikopoulos, G. J., Karpowicz, P. A., Seaberg, R. M., Dai, F. F., Lee, S., Ahrens, R., Fraser, P. E., et al. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.01.015 · Cited by 230
“…reports that the in vivo environment promotes differentiation/maturation of b cells from embryonic stem cell-derived endodermal pancreatic precursors (Kroon et al., 2008), we reasoned that we might be able to enhance mature b cell yield by using undifferentiated PMP spheres for transplantation.”
Kunisada, Y., Tsubooka-Yamazoe, N., Shoji, M., & Hosoya, M. (2011) · Stem Cell Research · doi:10.1016/j.scr.2011.10.002 · Cited by 228
“A large number of factors, including Cyclopamine-KAAD, (−)-indolactam V, Noggin, retinoic acid, FGF2, FGF4, FGF10, and EGF, have been reported to induce the differentiation of pancreatic progenitor cells (D'Amour et al., 2006; Kroon et al., 2008; Jiang et al., 2007; Chen et al., 2009; Cai et al.; Ameri et al.; Johanne…”
BackgroundMethodInfluentialSéguin, C. A., Draper, J. S., Nagy, A., & Rossant, J. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.06.018 · Cited by 214
Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges
Sneddon, J. B., Tang, Q., Stock, P. G., Bluestone, J. A., Roy, S., Desai, T. A., & Hebrok, M. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.05.016 · Cited by 252
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Clinical imaging in regenerative medicine
Naumova, A. V., Modo, M., Moore, A. V., Murry, C. E., & Frank, J. A. (2014) · Nature Biotechnology · doi:10.1038/nbt.2993 · Cited by 249
Bruin, J. E., Rezania, A., Xu, J., Narayan, K., Fox, J. K., O’Neil, J. J., & Kieffer, T. J. (2013) · Diabetologia · doi:10.1007/s00125-013-2955-4 · Cited by 216
How to make a functional β-cell
Pagliuca, F. W., & Melton, D. A. (2013) · Development · doi:10.1242/dev.093187 · Cited by 226
“If only a few cells are competent, this could explain why it takes 4 months for the transplanted graft to become functional and able to control diabetes in the host (Kroon et al., 2008; Rezania et al., 2012).”
BackgroundMethodInfluentialTEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors
Cebola, I., Rodríguez‐Seguí, S. A., Cho, C. H.-H., Bessa, J., Rovira, M., Luengo, M., Chhatriwala, M., Berry, A. A., Ponsa-Cobas, J., Maestro, M. A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3160 · Cited by 218
Metadata
- Authors
- Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., Agulnick, A. D., D'Amour, K. A., Carpenter, M. K., & Baetge, E. E.
- Venue
- Nature Biotechnology
- Published
- 2008-02-20
- Volume
- 26
- Issue
- 4
- Pages
- 443-452
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2106219965
- Cited by
- 1,843
- References
- 0
- Citations by year
- 2026: 26 · 2025: 44 · 2024: 46 · 2023: 88 · 2022: 67 · 2021: 81 · 2020: 85 · 2019: 76 · 2018: 87 · 2017: 98 · 2016: 122 · 2015: 116 · 2014: 156 · 2013: 168 · 2012: 154
- FWCI
- 150.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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 embryonic stem cells, beta cell differentiation, glucose-dependent insulin secretion, islet transplantation, diabetes cell therapy, C-peptide, proinsulin processing, streptozotocin-induced hyperglycemia
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Endoderm, Glucose, Humans, Insulin, Cell Culture Techniques, Pancreas, Artificial, Tissue Engineering, Cell Proliferation, Insulin-Secreting Cells, Mice, Embryonic Stem Cells
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