Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells

Stem Cell Reports. 2019 Feb 12;12(2):351-365. doi: 10.1016/j.stemcr.2018.12.012. Epub 2019 Jan 17.


Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic β cells. While these stem cell-derived β (SC-β) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor β (TGF-β) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-β cells that express β cell markers and undergo GSIS with first- and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-β signaling are required during SC-β cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.

Keywords: cell therapy; diabetes; differentiation; glucose-stimulated insulin secretion; human embryonic stem cells; human induced pluripotent stem cells; islets; pancreas; transplantation; β cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell- and Tissue-Based Therapy / methods
  • Cells, Cultured
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / physiology*
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Pancreas / metabolism
  • Pancreas / physiology
  • Pluripotent Stem Cells / metabolism
  • Pluripotent Stem Cells / physiology*
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / metabolism


  • Insulin
  • Transforming Growth Factor beta
  • Glucose