Cited by 472Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

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Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells

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Nair, Gopika G., Liu, Jennifer S., Russ, Holger A., Tran, Stella, Saxton, Michael S., Chen, Richard, Juang, Charity, Li, Mei-lan, Nguyen, Vinh Q., Giacometti, Simone, Puri, Sapna, Xing, Yuan, Wang, Yong, Szot, Gregory L., Oberholzer, Jose, Bhushan, Anil, Hebrok, Matthias·2019·Nature Cell Biology

DOI 10.1038/s41556-018-0271-4PMC PMC6746427

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Abstract

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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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: Nair, Gopika G.
Russ, Holger A.
Tran, Stella
Nguyen, Vinh Q.
Puri, Sapna
Xing, Yuan
Wang, Yong
Szot, Gregory L.
Bhushan, Anil
Hebrok, Matthias
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2019-02
Volume: 21
Issue: 2
Pages: 263-274
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/s41556-018-0271-4
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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Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells

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