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.
Gopika G Nair  1 ,  Jennifer S Liu  1 ,  Holger A Russ  1  2 ,  Stella Tran  1  3 ,  Michael S Saxton  1 ,  Richard Chen  1 ,  Charity Juang  1 ,  Mei-Lan Li  1 ,  Vinh Q Nguyen  4 ,  Simone Giacometti  1 ,  Sapna Puri  1 ,  Yuan Xing  5 ,  Yong Wang  5 ,  Gregory L Szot  4 ,  Jose Oberholzer  5 ,  Anil Bhushan  1 ,  Matthias Hebrok  6
Affiliations
  • 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. [email protected].
PMID: 30710150 DOI: 10.1038/s41556-018-0271-4
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.