Robust differentiation of human enteroendocrine cells from intestinal stem cells

Nat Commun. 2022 Jan 11;13(1):261. doi: 10.1038/s41467-021-27901-5.


Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of the endocannabinoid receptor signaling pathway, JNK, and FOXO1, known to mediate endodermal development and/or hormone production, together with directed differentiation of human ISCs from the duodenum and rectum. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, GIP, CCK, GLP-1 and PYY upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics.

Publication types

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

MeSH terms

  • Anthracenes / pharmacology
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology*
  • Chromogranin A / metabolism
  • Endocannabinoids / pharmacology
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / metabolism*
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Intestinal Mucosa / metabolism
  • Peptide YY / metabolism
  • Quinolones / pharmacology
  • Rimonabant / pharmacology
  • Signal Transduction
  • Somatostatin / metabolism
  • Stem Cells / drug effects*
  • Stem Cells / metabolism*
  • Transcription Factors / metabolism


  • 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  • Anthracenes
  • CHGA protein, human
  • Chromogranin A
  • Endocannabinoids
  • Quinolones
  • SST protein, human
  • Transcription Factors
  • Peptide YY
  • pyrazolanthrone
  • Somatostatin
  • Glucagon-Like Peptide 1
  • Rimonabant