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Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells
Open accessAbstract
Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic β cells. While these stem cell-derived β (SC-β) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor β (TGF-β) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-β cells that express β cell markers and undergo GSIS with first- and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-β signaling are required during SC-β cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.
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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 [42]
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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 [42]
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Mimicking nature-made beta cells: recent advances towards stem cell-derived islets
Tremmel, D. M., Mitchell, S. A., Sackett, S. D., & Odorico, J. S. (2019) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000687 · Cited by 37
Deciphering the Complex Communication Networks That Orchestrate Pancreatic Islet Function
Weitz, J., Menegaz, D., & Caicedo, A. (2020) · Diabetes · doi:10.2337/dbi19-0033 · Cited by 39
Development of a scalable method to isolate subsets of stem cell-derived pancreatic islet cells
Parent, A. V., Ashe, S., Nair, G. G., Li, M.-L., Chavez, J., Liu, J. S., Zhong, Y., Streeter, P. R., & Hebrok, M. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.02.001 · Cited by 37
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03574-3 · Cited by 36
Basile, G., Kahraman, S., Dirice, E., Pan, H., Dreyfuss, J. M., & Kulkarni, R. N. (2021) · Genome Medicine · doi:10.1186/s13073-021-00941-8 · Cited by 33
Krentz, N. A. J., Shea, L. D., Huising, M. O., & Shaw, J. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00170-4 · Cited by 39
A Century-long Journey From the Discovery of Insulin to the Implantation of Stem Cell–derived Islets
Ramzy, A., Belmonte, P. J., Braam, M. J. S., Ida, S., Wilts, E. M., Levings, M. K., Rezania, A., & Kieffer, T. J. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac021 · Cited by 37
Pancreatic β-Cell Development and RegenerationPreprint
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SUR1-mutant iPS cell-derived islets recapitulate the pathophysiology of congenital hyperinsulinism
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Genetic Engineering of Immune Evasive Stem Cell-Derived Islets
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Pancreatic β-cell heterogeneity in adult human islets and stem cell-derived islets
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The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells
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Generation of Pancreatic Progenitors from Human Pluripotent Stem Cells by Small Molecules
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Self-citationEncapsulation and immune protection for type 1 diabetes cell therapy
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Genome editing of human pancreatic beta cell models: problems, possibilities and outlook
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Bioprinting of bespoke islet-specific niches to promote maturation of stem cell-derived islets
Kim, M., Cho, S., Hwang, D. G., Shim, I. K., Kim, S. C., Jang, J., & Jang, J. (2025) · Nature Communications · doi:10.1038/s41467-025-56665-5 · Cited by 32
Metadata
- Authors
- Velazco-Cruz, L., Song, J., Maxwell, K. G., Goedegebuure, M. M., Augsornworawat, P., Hogrebe, N. J., & Millman, J. R.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Millman, Jeffrey R.
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 12
- Issue
- 2
- Pages
- 351-365
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC6372986
- OpenAlex
- W2910245538
- Cited by
- 399
- References
- 57
- Citations by year
- 2026: 45 · 2025: 49 · 2024: 54 · 2023: 56 · 2022: 61 · 2021: 72 · 2020: 42 · 2019: 20
- FWCI
- 46.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (5R01DK114233, 5P30DK020579, 2R25GM103757, 5T32DK108742, 5T32DK007120)
- JDRF (5-CDA-2017-391-A-N)
- Washington University Center of Regenerative Medicine
- Washington University School of Medicine
- Hope Center Viral Vectors Core
- 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
- stem cell-derived beta cells, human pluripotent stem cells, glucose-stimulated insulin secretion, TGF-beta signaling, beta cell differentiation, serum-free medium, islet transplantation, glucose tolerance, diabetes cell therapy
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Glucose, Humans, Insulin, Pancreas, Signal Transduction, Transforming Growth Factor beta, Pluripotent Stem Cells, Insulin-Secreting Cells, Mice, Embryonic Stem Cells, Cell- and Tissue-Based Therapy
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