Chemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional β cells

Nat Commun. 2021 Jun 7;12(1):3330. doi: 10.1038/s41467-021-23525-x.


Human pluripotent stem cell (hPSC)-derived pancreatic β cells are an attractive cell source for treating diabetes. However, current derivation methods remain inefficient, heterogeneous, and cell line dependent. To address these issues, we first devised a strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered 10 chemicals that not only retain the pancreatic progenitors in 3D clusters but also enhance their potentiality towards NKX6.1+/INS+ β cells. We further systematically screened signaling pathway modulators in the three steps from pancreatic progenitors toward β cells. The implementation of all these strategies and chemical combinations resulted in generating β cells from different sources of hPSCs with high efficiency. The derived β cells are functional and can reverse hyperglycemia in mice within two weeks. Our protocol provides a robust platform for studying human β cells and developing hPSC-derived β cells for cell replacement therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Line
  • Cell- and Tissue-Based Therapy
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus, Experimental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Pancreas / metabolism*
  • Pluripotent Stem Cells / metabolism*
  • Signal Transduction


  • Homeodomain Proteins
  • NKX6-1 protein, human