Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis

Ruixue Liu, Richard Moriggl, Dongsheng Zhang, Haifeng Li, Rebekah Karns, Hai Bin Ruan, Haitao Niu, Christopher Mayhew, Carey Watson, Hansraj Bangar, Sang wook Cha, David Haslam, Tongli Zhang, Shila Gilbert, Na Li, Michael Helmrath, James Wells, Lee Denson, Xiaonan Han

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 + Lgr5 2 CD24 + Lyso + or cKit + niche cells, which imprinted Lgr5 hi Ki67 + 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 languageEnglish (US)
Article numbere201900296
JournalLife science alliance
Volume2
Issue number2
DOIs
StatePublished - 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.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

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