Tuft cells act as regenerative stem cells in the human intestine

• 成果类型: Article
• 署名作者: Huang, Lulu; Bernink, Jochem H.; Giladi, Amir; Krueger, Daniel; van Son, Gijs J. F.; Geurts, Maarten H.; Busslinger, Georg; Lin, Lin; Begthel, Harry; Zandvliet, Maurice; Buskens, Christianne J.; Bemelman, Willem A.; Lopez-Iglesias, Carmen; Peters, Peter J.; Clevers, Hans
• 署名单位: Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); University of Amsterdam; Princess Maxima Center; Utrecht University; University of Amsterdam; Maastricht University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4466
• DOI: 10.1038/s41586-024-07952-6
• 发表日期: 2024-10-24
• 页码: 929-+
• 关键词: human colon; immunity; lineage; generation; reveal; atlas

摘要

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 mice(2-4). 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.