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

impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain , 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...

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Bibliographic Details
Published in:Life science alliance 2019-04, Vol.2 (2), p.e201900296
Main Authors: Liu, Ruixue, Moriggl, Richard, Zhang, Dongsheng, Li, Haifeng, Karns, Rebekah, Ruan, Hai-Bin, Niu, Haitao, Mayhew, Christopher, Watson, Carey, Bangar, Hansraj, Cha, Sang-Wook, Haslam, David, Zhang, Tongli, Gilbert, Shila, Li, Na, Helmrath, Michael, Wells, James, Denson, Lee, Han, Xiaonan
Format: Article
Language:English
Subjects:
Animals
beta Catenin - metabolism
Cell Differentiation
Cells, Cultured
Clostridioides difficile
Colitis - metabolism
Colitis - microbiology
Disease Models, Animal
Female
Humans
Induced Pluripotent Stem Cells - metabolism
Induced Pluripotent Stem Cells - microbiology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Organoids - metabolism
Organoids - microbiology
Paneth Cells - metabolism
Paneth Cells - microbiology
STAT5 Transcription Factor - metabolism
Stem Cell Niche - physiology
Tumor Suppressor Proteins - metabolism
Wnt Signaling Pathway
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Summary:impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain , 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 infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to 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 Lgr5 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 ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.
ISSN:2575-1077
2575-1077
DOI:10.26508/lsa.201900296