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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, View ORCID ProfileXiaonan Han  Correspondence email
Ruixue Liu
2Key Laboratory of Human Disease Comparative Medicine, the Ministry of Health, Institute of Laboratory Animal Sciences, Chinese Academy Institute of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
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Richard Moriggl
3Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
4Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
5Medical University of Vienna, Vienna, Austria
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Dongsheng Zhang
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, USA
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Haifeng Li
2Key Laboratory of Human Disease Comparative Medicine, the Ministry of Health, Institute of Laboratory Animal Sciences, Chinese Academy Institute of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
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Rebekah Karns
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, USA
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Hai-Bin Ruan
6Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MI, USA
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Haitao Niu
2Key Laboratory of Human Disease Comparative Medicine, the Ministry of Health, Institute of Laboratory Animal Sciences, Chinese Academy Institute of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
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Christopher Mayhew
7Division of Developmental Biology, CCHMC, Cincinnati, OH, USA
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Carey Watson
8Division of Pediatric Surgery, CCHMC, Cincinnati, OH, USA
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Hansraj Bangar
9Division of Infectious Diseases, CCHMC, Cincinnati, OH, USA
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Sang-wook Cha
7Division of Developmental Biology, CCHMC, Cincinnati, OH, USA
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David Haslam
9Division of Infectious Diseases, CCHMC, Cincinnati, OH, USA
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Tongli Zhang
12Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, OH, USA
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Shila Gilbert
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, USA
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Na Li
2Key Laboratory of Human Disease Comparative Medicine, the Ministry of Health, Institute of Laboratory Animal Sciences, Chinese Academy Institute of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
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Michael Helmrath
8Division of Pediatric Surgery, CCHMC, Cincinnati, OH, USA
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James Wells
7Division of Developmental Biology, CCHMC, Cincinnati, OH, USA
10Division of Endocrinology, CCHMC, Cincinnati, OH, USA
11Center for Stem Cell and Organoid Medicine, CCHMC, Cincinnati, OH, USA
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Lee Denson
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, USA
13Department of Pediatrics, University of Cincinnati College of Medicine, OH, USA
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Xiaonan Han
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, USA
2Key Laboratory of Human Disease Comparative Medicine, the Ministry of Health, Institute of Laboratory Animal Sciences, Chinese Academy Institute of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
13Department of Pediatrics, University of Cincinnati College of Medicine, OH, USA
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  • ORCID record for Xiaonan Han
  • For correspondence: xiaonan.han@cchmc.org
Published 4 April 2019. DOI: 10.26508/lsa.201900296
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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.

  • Received January 8, 2019.
  • Revision received March 27, 2019.
  • Accepted March 27, 2019.
  • © 2019 Liu et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Regulation of niche cell differentiation
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
Life Science Alliance Apr 2019, 2 (2) e201900296; DOI: 10.26508/lsa.201900296

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Regulation of niche cell differentiation
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
Life Science Alliance Apr 2019, 2 (2) e201900296; DOI: 10.26508/lsa.201900296
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Volume 2, No. 2
April 2019
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