Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells
Abstract
Transplantation of pancreatic progenitors or insulin-secreting cells derived from human embryonic stem cells (hESCs) has been proposed as a therapy for diabetes. We describe a seven-stage protocol that efficiently converts hESCs into insulin-producing cells. Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro. Additional characterization using single-cell imaging and dynamic glucose stimulation assays revealed similarities but also notable differences between S7 insulin-secreting cells and primary human beta cells. Nevertheless, S7 cells rapidly reversed diabetes in mice within 40 days, roughly four times faster than pancreatic progenitors. Therefore, although S7 cells are not fully equivalent to mature beta cells, their capacity for glucose-responsive insulin secretion and rapid reversal of diabetes in vivo makes them a promising alternative to pancreatic progenitor cells or cadaveric islets for the treatment of diabetes.
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A beta-like cell with behavior that fully recapitulates the physiology of a normal beta cell is yet to be realized.
“While a beta-like cell with behavior that fully recapitulates the physiology of a normal beta cell is yet to be realized”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [137]
There has been a steady series of improvements to directed differentiation strategies for generating beta-like cells over the past 20 years.
“there has been a steady series of improvements to directed differentiation strategies over the past 20 years135–138.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [137]
These SC-β cells have been shown to improve glycemic control in diabetic mice.
“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 [37]
In 2014-15, several groups published protocols for generating stem cell-derived β (SC-β) cells that secreted insulin in response to glucose stimulation.
“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 [37]
Transplantation of SC-islets into mice improves their insulin secretion and glucose responsiveness, suggesting that SC-islet immaturity can be resolved.
“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 [37]
The air-liquid interface protocol robustly generates functional SC-islets in a lab setting, but this culture system would be difficult to adapt to large-scale manufacturing.
“While this protocol is able to robustly generate functional SC-islets in a lab setting, this air-liquid interface culture system would be difficult to adapt to large-scale manufacturing.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [37]
One popular methodology uses planar culture for making PDX1+/NKX6-1+ pancreatic progenitors and then clusters cells on an air-liquid interface for endocrine induction and β cell maturation.
“For example, one popular methodology uses planar culture for making PDX1+/NKX6-1+ pancreatic progenitors and then clusters cells on an air-liquid interface for endocrine induction and β cell maturation.37”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [37]
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.
“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 [69]
The first four stages produce proliferative cells; as the cells differentiate, they become less proliferative.
“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 [69]
Methods have been developed by which pluripotent stem cells can be differentiated into β-like cells by a series of steps in which differentiation factors are added.
“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 [69]
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- Authors
- Rezania, A., Bruin, J. E., Arora, P., Rubin, A., Batushansky, I., Asadi, A., O'Dwyer, S., Quiskamp, N., Mojibian, M., Albrecht, T., Yang, Y. H. C., Johnson, J. D., & Kieffer, T. J.
- Affiliations
- Janssen Research & Development (United States) (US)
- University of British Columbia (CA)
- Corresponding author
- Rezania, Alireza
- Kieffer, Timothy J
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2014-09-11
- Volume
- 32
- Issue
- 11
- Pages
- 1121-1133
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2032472678
- Cited by
- 1,575
- References
- 2
- Citations by year
- 2026: 80 · 2025: 120 · 2024: 122 · 2023: 137 · 2022: 160 · 2021: 166 · 2020: 153 · 2019: 137 · 2018: 134 · 2017: 125 · 2016: 131 · 2015: 98 · 2014: 10
- FWCI
- 120.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- 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
- diabetes reversal, insulin-producing cells, human embryonic stem cells, pancreatic beta cells, in vitro differentiation, glucose-stimulated insulin secretion, MafA, pancreatic progenitor cells, cell therapy
- MeSH terms
- Animals, Cell Differentiation, Diabetes Mellitus, Glucose, Humans, Insulin, Pancreas, Pluripotent Stem Cells, Insulin-Secreting Cells, Mice, Embryonic Stem Cells, Cell- and Tissue-Based Therapy
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