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Generation of Functional Human Pancreatic β Cells In Vitro
Open accessAbstract
The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice.
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“Transplantation of SC-islets into mice improves their insulin secretion and glucose responsiveness, suggesting that SC-islet immaturity can be resolved.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [36]
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“and the largest SC-islet differentiation that has been reported in literature was performed in 500 mL magnetic spinner flasks.36”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [36]
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“These stem cells begin as proliferative undifferentiated cells that are exposed to a series of cycles of growth and differentiation factors that lead to seven defined stages.”
From The future of type 1 diabetes therapy (2025) · cites this paper as [68]
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“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”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [36]
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“These cells have been shown to improve glycemic control in diabetic mice, highlighting their potential utility in vivo.36,37,39–44”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [36]
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“SC-islet protocols that are performed completely in suspension culture36 benefit from the natural three-dimensional scaling of these systems.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [36]
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“Methods have been developed (figure 2) by which pluripotent stem cells can be differentiated into βlike cells by a series of steps in which differentiation factors are added.68,69”
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“The first four stages produce proliferative cells.As the cells differentiate, they become less proliferative.”
From The future of type 1 diabetes therapy (2025) · cites this paper as [68]
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“For instance, Pagliuca and colleagues kept human embryonic stem cells suspended in liquid culture at 70 rpm, added specific growth factors to encourage differentiation, and found that the resulting beta-like cells behaved similarly to mature beta cells220.”
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Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673
Kriks, S., Shim, J., Piao, J., Ganat, Y. M., Wakeman, D. R., Xie, Z., Carrillo‐Reid, L., Auyeung, G., Antonacci, C. L., Buch, A., et al. (2011) · Nature · doi:10.1038/nature10648 · Cited by 1,951
International trial of the Edmonton protocol for islet transplantation
Shapiro, A. M. J., Ricordi, C., Hering, B. J., Auchincloss, H., Lindblad, R., Robertson, R. P., Secchi, A., Brendel, M. D., Berney, T., Brennan, D. C., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa061267 · Cited by 1,942
Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells
D’Amour, K. A., Bang, A. G., Eliazer, S., Kelly, O., Agulnick, A. D., Smart, N. G., Moorman, M. A., KROON, E. J., Carpenter, M. K., & Baetge, E. E. (2006) · Nature Biotechnology · doi:10.1038/nbt1259 · Cited by 1,913
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 5×
“Transplantation of pancreatic progenitors expressing PDX1+/ NKX6-1+ (PP2 in Figure 1A) into mice gives rise to functional b cells in vivo after 3–4 months (Kroon et al., 2008; Rezania et al., 2012).”
BackgroundResultInfluentialEfficient differentiation of human embryonic stem cells to definitive endoderm
D'Amour, K. A., Agulnick, A. D., Eliazer, S., Kelly, O. G., Kroon, E., & Baetge, E. E. (2005) · Nature Biotechnology · doi:10.1038/nbt1163 · Cited by 1,730
Keirstead, H. S., Nistor, G., Bernal, G. M., Totoiu, M. O., Cloutier, F., Sharp, K. L., & Steward, O. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0311-05.2005 · Cited by 1,263
Notch signalling controls pancreatic cell differentiation
Apelqvist, Å., Li, H., Sommer, L., Beatus, P., Anderson, D. J., Honjo, T., de Angelis, M. H., Lendahl, U., & Edlund, H. (1999) · Nature · doi:10.1038/23716 · Cited by 1,158
Induction of Pancreatic Differentiation by Signals from Blood Vessels
Lammert, E., Cleaver, O. B., & Melton, D. A. (2001) · Science · doi:10.1126/science.1064344 · Cited by 1,064
Self-citationNotch signaling controls multiple steps of pancreatic differentiation
Murtaugh, L. C., Stanger, B. Z., Kwan, K. M., & Melton, D. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2436557100 · Cited by 782
Self-citationHuman ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts
Shiba, Y., Fernandes, S., Zhu, W.-Z., Filice, D., Muskheli, V., Kim, J., Palpant, N. J., Gantz, J. A., Moyes, K. W., Reinecke, H., et al. (2012) · Nature · doi:10.1038/nature11317 · Cited by 769
Conversion of Mouse and Human Fibroblasts into Functional Spinal Motor Neurons
Son, E., Ichida, J. K., Wainger, B. J., Toma, J. S., Rafuse, V. F., Woolf, C. J., & Eggan, K. C. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.07.014 · Cited by 651
Rezania, A., Bruin, J. E., Riedel, M. J., Mojibian, M., Asadi, A., Xu, J., Gauvin, R., Narayan, K., Karanu, F., O’Neil, J. J., et al. (2012) · Diabetes · doi:10.2337/db11-1711 · Cited by 582
Yoshioka, M., Kayo, T., Ikeda, T., & Koizuni, A. (1997) · Diabetes · doi:10.2337/diab.46.5.887 · Cited by 536
A TALEN Genome-Editing System for Generating Human Stem Cell-Based Disease Models
Ding, Q., Lee, Y., Schaefer, E. A. K., Peters, D., Veres, A., Kim, K. J., Kuperwasser, N., Motola, D., Meissner, T. B., Hendriks, W. T. J., et al. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.11.011 · Cited by 515
Parsons, J. A. (1992) · Endocrinology · doi:10.1210/en.130.3.1459 · Cited by 476
Lü, B., Malcuit, C. M., Wang, S., Girman, S. V., Francis, P. J., Lemieux, L., Lanza, R., & Lund, R. D. (2009) · Stem Cells · doi:10.1002/stem.149 · Cited by 471
Schulz, T. C., Young, H. Y., Agulnick, A. D., Josephine Babin, M., Baetge, E. E., Bang, A. G., Bhoumik, A., Cepa, I., Cesario, R. M., Haakmeester, C., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037004 · Cited by 437
Regulation of pancreas development by hedgehog signaling
Hebrok, M., Kim, S. K., St-Jacques, B., McMahon, A. P., & Melton, D. A. (2000) · Development · doi:10.1242/dev.127.22.4905 · Cited by 412
Self-citationAssessing the potential of glucokinase activators in diabetes therapy
Matschinsky, F. M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2850 · Cited by 411
Nostro, M. C., Sarangi, F., Ogawa, S., Holtzinger, A., Corneo, B., Li, X., Micallef, S. J., Park, I., Basford, C., Wheeler, M. B., et al. (2011) · Development · doi:10.1242/dev.055236 · Cited by 386
Nkx6.1 Is Essential for Maintaining the Functional State of Pancreatic Beta Cells
Taylor, B. L., Liu, F., & Sander, M. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.010 · Cited by 360
Bellin, M. D., Barton, F. B., Heitman, A., Harmon, J. V., Kandaswamy, R., Balamurugan, A. N., Sutherland, D. E. R., Alejandro, R., & Hering, B. J. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03977.x · Cited by 350
Blum, B., Hrvatin, S., Schuetz, C., Bonal, C., Rezania, A., & Melton, D. (2012) · Nature Biotechnology · doi:10.1038/nbt.2141 · Cited by 349
Self-citationRodriguez‐Diaz, R., Dando, R., Jacques-Silva, M. C., Fachado, A., Molina, J., Abdulreda, M. H., Ricordi, C., Roper, S. D., Berggren, P., & Caicedo, A. (2011) · Nature Medicine · doi:10.1038/nm.2371 · Cited by 305
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 · cited 10×
“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-citationRezania, 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
Targeting the pancreatic β-cell to treat diabetes
Vetere, A., Choudhary, A., Burns, S. M., & Wagner, B. K. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4231 · Cited by 258
Xie, 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
Update on Islet Transplantation
McCall, M., & James Shapiro, A. M. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a007823 · Cited by 226
Embryogenesis of the Human Pancreatic Islets: A Light and Electron Microscopic Study
LIKE, A. A., & Orci, L. (1972) · Diabetes · doi:10.2337/diab.21.2.s511 · Cited by 214
Activin receptor patterning of foregut organogenesis
Kim, S. K., Hebrok, M., Li, E., Oh, S. P., Schrewe, H., Harmon, E. B., Lee, J. S., & Melton, D. A. (2000) · Genes & Development · doi:10.1101/gad.14.15.1866 · Cited by 212 · cited 2×
“Studies on pancreatic development in model organisms (Gamer and Wright, 1995; Henry and Melton, 1998; Ninomiya et al., 1999; Apelqvist et al., 1999; Kim et al., 2000; Hebrok et al., 2000; Murtaugh et al., 2003) identified genes and signals important for the pancreatic lineage, and these have been…”
BackgroundSelf-citationSelf-Renewing Endodermal Progenitor Lines Generated from Human Pluripotent Stem Cells
Cheng, X., Ying, L., Lü, L., Galvão, A. M., Mills, J. A., Lin, H. C., Kotton, D. N., Shen, S. S., Nostro, M. C., Choi, J. K., et al. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.02.024 · Cited by 205
Mixer , a Homeobox Gene Required for Endoderm Development
Henry, G. L., & Melton, D. A. (1998) · Science · doi:10.1126/science.281.5373.91 · Cited by 204
Self-citationA simple tool to improve pluripotent stem cell differentiation
Chetty, S., Pagliuca, F. W., Honoré, C., Kweudjeu, A., Rezania, A., & Melton, D. A. (2013) · Nature Methods · doi:10.1038/nmeth.2442 · Cited by 186
Self-citationBruin, J. E., Erener, S., Vela, J., Hu, X., Johnson, J. D., Kurata, H., Lynn, F., Piret, J., Asadi, A., Rezania, A., et al. (2014) · Stem Cell Research · doi:10.1016/j.scr.2013.10.003 · Cited by 162
Aguayo‐Mazzucato, C., Zavacki, A. M., Marinelarena, A. M., Hollister‐Lock, J., Khattabi, I. E., Marsili, A., Weir, G. C., Sharma, A., Larsen, P. R., & Bonner‐Weir, S. (2013) · Diabetes · doi:10.2337/db12-0849 · Cited by 153
Brelje, T. C., Stout, L. E., Bhagroo, N. V., & Sorenson, R. L. (2004) · Endocrinology · doi:10.1210/en.2004-0201 · Cited by 134
Gamer, L. W., & Wright, C. V. E. (1995) · Developmental Biology · doi:10.1006/dbio.1995.1275 · Cited by 134
Microfluidic device for multimodal characterization of pancreatic islets
Mohammed, J. S., Wang, Y., Harvat, T. A., Oberholzer, J., & Eddington, D. (2008) · Lab on a Chip · doi:10.1039/b809590f · Cited by 132
Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme
Sneddon, J. B., Borowiak, M., & Melton, D. (2012) · Nature · doi:10.1038/nature11463 · Cited by 129
Self-citationDiabetes Beyond Insulin: Review of New Drugs for Treatment of Diabetes Mellitus
Modi, P. J. (2007) · Current Drug Discovery Technologies · doi:10.2174/157016307781115476 · Cited by 95
Beneficial effects of prolactin and laminin on human pancreatic islet-cell cultures
Labriola, L., Montor, W. R., Krogh, K., Lojudice, F. H., Genzini, T., Goldberg, A. C., Eliaschewitz, F. G., & Sogayar, M. C. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.09.011 · Cited by 87
Narayanan, K., Lim, V. Y., Shen, J., Tan, Z. W., Rajendran, D., Luo, S.-C., Gao, S., Wan, A. C. A., & Ying, J. Y. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2013.0257 · Cited by 83
Brehm, M., Bortell, R., Diiorio, P., Leif, J., Laning, J., Cuthbert, A., Yang, C.-X., Herlihy, M., Burzenski, L., Gott, B., et al. (2010) · Diabetes · doi:10.2337/db10-0323 · Cited by 74
Self-citationThe ultrastructure of the human pancreatic islets
Deconinck, J., Potvliege, P. R., & Gepts, W. (1971) · Diabetologia · doi:10.1007/bf01211879 · Cited by 72
Minireview: Intraislet Regulation of Insulin Secretion in Humans
Rutter, G. A., & Hodson, D. J. (2013) · Molecular Endocrinology · doi:10.1210/me.2013-1278 · Cited by 69
Large human islets secrete less insulin per islet equivalent than smaller islets in vitro
Fujita, Y., Takita, M., Shimoda, M., Itoh, T., Sugimoto, K., Noguchi, H., Naziruddin, B., Levy, M. F., & Matsumoto, S. (2011) · Islets · doi:10.4161/isl.3.1.14131 · Cited by 61
Endoderm differentiation and inductive effect of activin‐treated ectoderm in Xenopus
Ninomiya, H., Takahashi, S., Tanegashima, K., Yokota, C., & Asashima, M. (1999) · Development Growth & Differentiation · doi:10.1046/j.1440-169x.1999.00449.x · Cited by 37
Thowfeequ, S., Ralphs, K. L., Yu, W., Slack, J. M. W., & Tosh, D. (2007) · Diabetologia · doi:10.1007/s00125-007-0724-y · Cited by 35
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Baron, M., Veres, A., Wolock, S. L., Faust, A. L., Gaujoux, R., Vetere, A., Ryu, J. H., Wagner, B. K., Shen-Orr, S. S., Klein, A. M., et al. (2016) · Cell Systems · doi:10.1016/j.cels.2016.08.011 · Cited by 1,508
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Metadata
- Authors
- Pagliuca, F. W., Millman, J. R., Gürtler, M., Segel, M., Van Dervort, A., Ryu, J. H., Peterson, Q. P., Greiner, D., & Melton, D. A.
- Affiliations
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Melton, Douglas A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 159
- Issue
- 2
- Pages
- 428-439
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4617632
- OpenAlex
- W2148890861
- Cited by
- 2,025
- References
- 50
- Citations by year
- 2026: 104 · 2025: 147 · 2024: 152 · 2023: 159 · 2022: 183 · 2021: 196 · 2020: 185 · 2019: 168 · 2018: 175 · 2017: 181 · 2016: 200 · 2015: 157 · 2014: 16
- FWCI
- 183.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1uc4dk104218-01)
- Harvard Stem Cell Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (UC4-DK-104218, U01DK089572, P30DK020593)
- 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
- pancreatic beta cells, human pluripotent stem cells, stem cell-derived beta cells, glucose-dependent insulin secretion, beta cell differentiation, insulin secretion, calcium flux, cell transplantation, diabetes mellitus, hyperglycemia, secretory granules
- MeSH terms
- Animals, Humans, Insulin, Islets of Langerhans, Cell Culture Techniques, Pluripotent Stem Cells, Insulin-Secreting Cells, Mice, Induced Pluripotent Stem Cells
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