TY - JOUR T1 - Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control <em>Clostridium difficile</em> colitis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900296 VL - 2 IS - 2 SP - e201900296 AU - Ruixue Liu AU - Richard Moriggl AU - Dongsheng Zhang AU - Haifeng Li AU - Rebekah Karns AU - Hai-Bin Ruan AU - Haitao Niu AU - Christopher Mayhew AU - Carey Watson AU - Hansraj Bangar AU - Sang-wook Cha AU - David Haslam AU - Tongli Zhang AU - Shila Gilbert AU - Na Li AU - Michael Helmrath AU - James Wells AU - Lee Denson AU - Xiaonan Han Y1 - 2019/04/01 UR - https://www.life-science-alliance.org/content/2/2/e201900296.abstract N2 - 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. ER -