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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / physiology
  • Endocrine Cells / cytology*
  • Endocrine Cells / physiology
  • Fibroblasts / cytology*
  • Fibroblasts / physiology
  • Glucose / pharmacology
  • Human Embryonic Stem Cells / cytology*
  • Human Embryonic Stem Cells / physiology
  • Humans
  • Insulin Secretion / drug effects
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans / cytology
  • Mice
  • Mitochondria / metabolism


  • Glucose