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Robust differentiation of human enteroendocrine cells from intestinal stem cells

Author

Listed:
  • Daniel Zeve

    (Boston Children’s Hospital
    Harvard Medical School)

  • Eric Stas

    (Boston Children’s Hospital)

  • Joshua Sousa Casal

    (Boston Children’s Hospital
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • 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
    Center for Nanomedicine and Division of Engineering in Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology
    Tongji University)

  • Sarah Dubois

    (Boston Children’s Hospital
    MCPHS University)

  • Manasvi S. Shah

    (Boston Children’s Hospital
    Harvard Medical School)

  • Erin P. Syverson

    (Harvard Medical School
    Boston Children’s Hospital)

  • Sophie Hafner

    (Boston Children’s Hospital)

  • Jeffrey M. Karp

    (Broad Institute of MIT and Harvard
    Center for Nanomedicine and Division of Engineering in Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology
    Harvard Stem Cell Institute)

  • Diana L. Carlone

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Jose Ordovas-Montanes

    (Boston Children’s Hospital
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Stem Cell Institute)

  • David T. Breault

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute)

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.

Suggested Citation

  • 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, 2022. "Robust differentiation of human enteroendocrine cells from intestinal stem cells," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27901-5
    DOI: 10.1038/s41467-021-27901-5
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    Cited by:

    1. Songhai Tian & Xiaozhe Xiong & Ji Zeng & Siyu Wang & Benjamin Jean-Marie Tremblay & Peng Chen & Baohua Chen & Min Liu & Pengsheng Chen & Kuanwei Sheng & Daniel Zeve & Wanshu Qi & David T. Breault & Cé, 2022. "Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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