Robust differentiation of human enteroendocrine cells from intestinal stem cells

Daniel Zeve, Eric Stas, Joshua Sousa Casal, Prabhath Mannam, Wanshu Qi, Xiaolei Yin, Sarah Dubois, Manasvi S. Shah, Erin P. Syverson, Sophie Hafner, Jeffrey M. Karp, Diana L. Carlone, Jose Ordovas-Montanes and David T. Breault ()
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Daniel Zeve: Boston Children’s Hospital
Eric Stas: Boston Children’s Hospital
Joshua Sousa Casal: Boston Children’s Hospital
Prabhath Mannam: Boston Children’s Hospital
Wanshu Qi: Boston Children’s Hospital
Xiaolei Yin: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Sarah Dubois: Boston Children’s Hospital
Manasvi S. Shah: Boston Children’s Hospital
Erin P. Syverson: Harvard Medical School
Sophie Hafner: Boston Children’s Hospital
Jeffrey M. Karp: Broad Institute of MIT and Harvard
Diana L. Carlone: Boston Children’s Hospital
Jose Ordovas-Montanes: Boston Children’s Hospital
David T. Breault: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27901-5

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