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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”
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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.”
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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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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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