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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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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”
From The future of type 1 diabetes therapy (2025) · cites this paper as [68]
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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]
Experimental — accuracy not yet measuredIn the citing paper
“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.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [220]
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Citations
Cites
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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
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“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
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Notch signalling controls pancreatic cell differentiation
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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
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Items 1,001–1,004 of 1,004
Engineering islets from stem cells: The optimal solution for the treatment of diabetes
Du, S., Li, Y., Geng, Z., Zhang, Q., Buhler, L. H., Gonelle-Gispert, C., & Wang, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.869514 · Cited by 9
Yehya, H., Wells, A., Majcher, M., Nakhwa, D., King, R., Senturk, F., Padmanabhan, R., Jensen, J., & Bukys, M. A. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03973-0 · Cited by 7
Human iPSC Models in Drug Discovery: Opportunities and Challenges
Silva, M. C., Cross, A., Brandon, N. J., & Haggarty, S. J. (2017) · Comprehensive Medicinal Chemistry III · doi:10.1016/b978-0-12-409547-2.12284-x · Cited by 6
Massively parallel functional genomic assays in endocrinology: from promise to delivery
Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
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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