Activated STAT5 confers resistance to intestinal injury by increasing intestinal stem cell proliferation and regeneration

Stem Cell Reports. 2015 Feb 10;4(2):209-25. doi: 10.1016/j.stemcr.2014.12.004. Epub 2015 Jan 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation* / genetics
  • Cell Proliferation
  • Colitis / etiology
  • Colitis / pathology
  • Disease Models, Animal
  • Gene Targeting
  • Genetic Loci
  • Genetic Vectors / genetics
  • Humans
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / physiology*
  • Intestinal Mucosa / radiation effects
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Polycomb Repressive Complex 1 / genetics
  • Protein Binding
  • Radiation Injuries
  • Radiation Injuries, Experimental
  • Radiation Tolerance / genetics
  • Regeneration* / genetics
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism*
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Transcriptional Activation

Substances

  • STAT5 Transcription Factor
  • Polycomb Repressive Complex 1