@article {Liue201900296, author = {Ruixue Liu and Richard Moriggl and Dongsheng Zhang and Haifeng Li and Rebekah Karns and Hai-Bin Ruan and Haitao Niu and Christopher Mayhew and Carey Watson and Hansraj Bangar and Sang-wook Cha and David Haslam and Tongli Zhang and Shila Gilbert and Na Li and Michael Helmrath and James Wells and Lee Denson and Xiaonan Han}, title = {Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis}, volume = {2}, number = {2}, elocation-id = {e201900296}, year = {2019}, doi = {10.26508/lsa.201900296}, publisher = {Life Science Alliance}, 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-CD24+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.}, URL = {https://www.life-science-alliance.org/content/2/2/e201900296}, eprint = {https://www.life-science-alliance.org/content/2/2/e201900296.full.pdf}, journal = {Life Science Alliance} }