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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A large body of work has focused on developing the ideal cellular niche and encapsulation strategies to support normal patterns of hormone secretion while protecting cellular implants from autoimmune destruction.
“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]
The Abstract reports that endocrine-cell clustering produced β-cell clusters with robust dynamic insulin secretion, supporting the cellular-niche and hormone-secretion part of the claim. The Results section on transplantation reports functional grafts, but our copy does not describe encapsulation strategies or protection from autoimmune destruction; the kidney capsule is a transplant site, not an encapsulation strategy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTransplantation 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 [44]
The Results section, “Rapid onset of eBC functionality in vivo within days of transplantation” (page unavailable), reports glucose-responsive C-peptide secretion three days after transplantation and higher secretion eight months later. But the paper attributes the acquisition of mature glucose responsiveness chiefly to clustering in culture: the transplanted eBCs were already functional. It therefore does not establish that transplantation itself resolves SC-islet immaturity. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSC-islets generated in vitro remain transcriptionally and functionally immature compared to adult human islets.
“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]
The Discussion says earlier hPSC-derived β-like cells appeared immature in transcript and functional analyses. But it also reports that the paper’s reaggregated cells gained adult-islet-like functional properties; although some adult β-cell markers and insulin output remained lower, the unqualified claim that in-vitro-generated SC-islets remain functionally immature overstates the paper’s findings. No page numbers are provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThese 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 [44]
Significant progress has been made at improving the function of SC-islets when compared to the original protocols.
“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]
A similar process was used by Nair and colleagues using mechanical agitation to keep human cells suspended in culture, resulting in functional beta-like clusters.
“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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- 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 › 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
- 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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