Tuft cells act as regenerative stem cells in the human intestine

Lulu Huang, Jochem H. Bernink (), Amir Giladi, Daniel Krueger, Gijs J. F. Son, Maarten H. Geurts, Georg Busslinger, Lin Lin, Harry Begthel, Maurice Zandvliet, Christianne J. Buskens, Willem A. Bemelman, Carmen López-Iglesias, Peter J. Peters and Hans Clevers ()
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Lulu Huang: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Jochem H. Bernink: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Amir Giladi: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Daniel Krueger: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Gijs J. F. Son: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Maarten H. Geurts: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Georg Busslinger: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Lin Lin: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Harry Begthel: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Maurice Zandvliet: Utrecht University
Christianne J. Buskens: Amsterdam Gastroenterology Endocrinology Metabolism
Willem A. Bemelman: Amsterdam Gastroenterology Endocrinology Metabolism
Carmen López-Iglesias: Maastricht University
Peter J. Peters: Maastricht University
Hans Clevers: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht

Nature, 2024, vol. 634, issue 8035, 929-935

Abstract: Abstract 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. 1). 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 mice2–4. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07952-6

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