Robust differentiation of human enteroendocrine cells from intestinal stem cells.
Daniel ZeveEric StasJoshua De Sousa CasalPrabhath MannamWanshu QiXiaolei YinSarah DuboisManasvi S ShahErin P SyversonSophie HafnerJeffrey M KarpDiana L CarloneJosé Ordovas-MontañesDavid T BreaultPublished in: Nature communications (2022)
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.
Keyphrases
- induced apoptosis
- signaling pathway
- stem cells
- endothelial cells
- small molecule
- cell cycle arrest
- endoplasmic reticulum stress
- induced pluripotent stem cells
- pi k akt
- oxidative stress
- cell death
- cell therapy
- epithelial mesenchymal transition
- drug delivery
- single cell
- cancer therapy
- protein protein
- cell proliferation
- artificial intelligence