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Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells
Open accessAbstract
Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional β cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and β cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature β-like cells to form islet-sized enriched β-clusters (eBCs). eBCs display physiological properties analogous to primary human β cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus-secretion coupling in mature β cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived β cells that resemble their endogenous counterparts.
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“In parallel, a large body of work has focused on developing the ideal cellular niche and encapsulation strategies to support normal patterns of hormone secretion while also protecting these cellular implants from autoimmune destruction139,140.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [140]
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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 [44]
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“SC-islets generated in vitro remain transcriptionally and functionally immature compared to adult human islets.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [44]
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“A similar process was used by Nair and colleagues using mechanical agitation to keep human cells suspended in culture, resulting in functional beta-like clusters221.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [221]
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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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“To this end, significant progress has been made at improving the function of SC-islets when compared to the original protocols,39,40,44,48,49”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [44]
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Metadata
- Authors
- Nair, G. G., Liu, J. S., Russ, H. A., Tran, S., Saxton, M. S., Chen, R., Juang, C., Li, M.-L., Nguyen, V. Q., Giacometti, S., Puri, S., Xing, Y., Wang, Y., Szot, G. L., Oberholzer, J., Bhushan, A., & Hebrok, M.
- Affiliations
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- University of Virginia (US)
- Corresponding author
- Hebrok, Matthias
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-02
- Volume
- 21
- Issue
- 2
- Pages
- 263-274
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6746427
- OpenAlex
- W2913837249
- Cited by
- 472
- References
- 45
- Citations by year
- 2026: 39 · 2025: 51 · 2024: 67 · 2023: 69 · 2022: 73 · 2021: 85 · 2020: 57 · 2019: 31
- FWCI
- 59.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-03-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DK108666)
- University of California, San Francisco
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK108666, P30DK063720, R01DK105831)
- 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
- beta cell maturation, stem cell-derived beta cells, human embryonic stem cells, insulin secretion, calcium signaling, glucose-stimulated insulin secretion, islet transplantation
- MeSH terms
- Human Embryonic Stem Cells, Insulin Secretion, Animals, Cell Differentiation, Cells, Cultured, Fibroblasts, Glucose, Humans, Islets of Langerhans, Mitochondria, Insulin-Secreting Cells, Mice, Embryonic Stem Cells, Endocrine Cells
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