Abstract
Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain C. difficile, Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell (IESC) regeneration. However, how IESCs are sustained to specify Paneth-like cells as their niche remains unclear. Cytokine-JAK-STATs are required for IESC regeneration. We investigated how constitutive STAT5 activation (Ca-pYSTAT5) restricts IESC differentiation towards niche cells to restrain C. difficile infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on C. difficile colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis. In contrast, Ca-pYSTAT5 enhanced Paneth cell lineage tracing and restricted Lgr5 IESC differentiation towards pYSTAT5+Lgr52CD24+Lyso+ or cKit+ niche cells, which imprinted Lgr5hiKi67+ IESCs. Mechanistically, pYSTAT5 activated Wnt/β-catenin signaling to determine Paneth cell fate. In conclusion, Ca-pYSTAT5 gradients control niche differentiation. Lack of pYSTAT5 reduces the niche cells to sustain IESC regeneration and induces C. difficile ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.
Original language | English (US) |
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Article number | e201900296 |
Journal | Life science alliance |
Volume | 2 |
Issue number | 2 |
DOIs | |
State | Published - 2019 |
Bibliographical note
Funding Information:This work was supported by Crohn’s Colitis Foundation of America Senior Research Award (426234, to X Han), NIAID R21 (AI103388 to X Han) and Cincinnati Children’s Hospital Research Foundation Digestive Health Center (P30DK078392), NIH R01 (DK098231) (to L Denson), USA, and Peking Union Medical College Professor Scholar (2016RC310011 to X Han), P.R. China. R Moriggl was supported by a private cancer metabolism grant donation from Liechtenstein and the Austrian Science Fund (FWF), grants SFB F4707 and SFB-F06105, Austria.
Publisher Copyright:
© 2019 Liu et al.