Tuft cells act as regenerative stem cells in the human intestine
In mice, intestinal tuft cells have been described as a long-lived, postmitotic cell type. Two distinct subsets have been identified: tuft-1 and tuft-2 (ref. <sup>1</sup>). By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase on interleukin-4 (IL-4) and IL-13 exposure, as reported previously in mice<sup>2-4</sup>. This occurs through proliferation of pre-existing tuft cells, rather than through increased de novo generation from stem cells. Indeed, proliferative tuft cells occur in vivo both in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans.
Authors
- Amir Giladi (ORCID: https://orcid.org/0000-0002-5880-2845)
- Georg Busslinger (ORCID: https://orcid.org/0000-0002-7851-9895)
- Carmen López‐Iglesias
- Lulu Huang (ORCID: https://orcid.org/0009-0007-5709-6874)
- Peter J. Peters (ORCID: https://orcid.org/0000-0002-2964-5684)
- Daniel Krueger (ORCID: https://orcid.org/0000-0003-1139-7755)
- Jochem H. Bernink (ORCID: https://orcid.org/0000-0001-9332-9224)
- Willem A. Bemelman (ORCID: https://orcid.org/0000-0002-1037-9945)
- Lin Lin (ORCID: https://orcid.org/0009-0001-6308-6804)
- Hans Clevers (ORCID: https://orcid.org/0000-0002-3077-5582)
- Christianne J. Buskens (ORCID: https://orcid.org/0000-0001-9425-8683)
- Maarten H. Geurts (ORCID: https://orcid.org/0009-0006-8832-3745)
- Gijs J. F. van Son (ORCID: https://orcid.org/0000-0003-0572-3243)
- Maurice M.J.M. Zandvliet (ORCID: https://orcid.org/0000-0002-0542-5433)
- Harry Begthel (ORCID: https://orcid.org/0009-0008-1888-9502)
Institutions
- Roche (Switzerland) (CH)
- Royal Netherlands Academy of Arts and Sciences (NL)
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- Maastricht University (NL)
- Amsterdam Neuroscience (NL)
- Oncode Institute (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- Princess Máxima Center (NL)
- Amsterdam University Medical Centers (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s41586-024-07952-6
- Citations
- 64
- Primary Topic
- Magnetic and Electromagnetic Effects
- Type
- article
- Field-Weighted Citation Impact
- 25.76
Funders
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- China Scholarship Council