title: Activated STAT5 confers resistance to intestinal injury by increasing intestinal stem cell proliferation and regeneration.
abstract: Intestinal epithelial stem cells (IESCs) control the intestinal homeostatic response to inflammation and regeneration. The underlying mechanisms are unclear. Cytokine-STAT5 signaling regulates intestinal epithelial homeostasis and responses to injury. We link STAT5 signaling to IESC replenishment upon injury by depletion or activation of Stat5 transcription factor. We found that depletion of Stat5 led to deregulation of IESC marker expression and decreased LGR5(+) IESC proliferation. STAT5-deficient mice exhibited worse intestinal histology and impaired crypt regeneration after γ-irradiation. We generated a transgenic mouse model with inducible expression of constitutively active Stat5. In contrast to Stat5 depletion, activation of STAT5 increased IESC proliferation, accelerated crypt regeneration, and conferred resistance to intestinal injury. Furthermore, ectopic activation of STAT5 in mouse or human stem cells promoted LGR5(+) IESC self-renewal. Accordingly, STAT5 promotes IESC proliferation and regeneration to mitigate intestinal inflammation. STAT5 is a functional therapeutic target to improve the IESC regenerative response to gut injury.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Shila
authors.initials: S
authors.lastname: Gilbert
authors.affiliation: Institute of Animal Breeding and Genetics, Biomodels Austria, Institute of Laboratory Animal Science, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Harini
authors.initials: H
authors.lastname: Nivarthi
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Mayhew
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Lo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Taeko K
authors.initials: TK
authors.lastname: Noah
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jefferson
authors.initials: J
authors.lastname: Vallance
authors.affiliation: Institute of Animal Breeding and Genetics, Biomodels Austria, Institute of Laboratory Animal Science, University of Veterinary Medicine, 1210 Vienna, Austria; Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Institute of Animal Breeding and Genetics, Biomodels Austria, Institute of Laboratory Animal Science, University of Veterinary Medicine, 1210 Vienna, Austria; Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Tang
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Helmrath
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Shroyer
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Institute of Animal Breeding and Genetics, Biomodels Austria, Institute of Laboratory Animal Science, University of Veterinary Medicine, 1210 Vienna, Austria; Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: xiaonan.han@cchmc.org.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003092:Colitis / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D018390:Gene Targeting; D056426:Genetic Loci; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000473:pathology / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D011485:Protein Binding; D011832:Radiation Injuries; D011833:Radiation Injuries, Experimental; D011836:Radiation Tolerance / Q000235:genetics; D012038:Regeneration / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050799:STAT5 Transcription Factor; D063150:Polycomb Repressive Complex 1