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Nat Cell Biol. 2019 Feb;21(2):263-274. doi: 10.1038/s41556-018-0271-4. Epub 2019 Feb 1.

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

Author information

1
Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
2
Barbara Davis Center for Diabetes, University of Colorado, School of Medicine, Aurora, CO, USA.
3
Lawrence Berkeley National Laboratory, University of California-Berkeley, Berkeley, CA, USA.
4
Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
5
Department of Surgery/Division of Transplantation, University of Virginia, Charlottesville, VA, USA.
6
Diabetes Center, University of California San Francisco, San Francisco, CA, USA. mhebrok@diabetes.ucsf.edu.

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.

Comment in

PMID:
30710150
PMCID:
PMC6746427
[Available on 2020-02-01]
DOI:
10.1038/s41556-018-0271-4
[Indexed for MEDLINE]

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