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Stem Cell Reports. 2018 Jan 9;10(1):17-26. doi: 10.1016/j.stemcr.2017.11.015. Epub 2017 Dec 21.

JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation.

Author information

1
Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: camilla.richmond@childrens.harvard.edu.
2
Division of Endocrinology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
3
Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
4
Division of Endocrinology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
5
Division of Endocrinology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

Abstract

The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.

KEYWORDS:

CD3; JAK/STAT; STAT-1; dormant; inflammation; intestinal stem cells; quiescent; reserve

PMID:
29276155
PMCID:
PMC5768934
DOI:
10.1016/j.stemcr.2017.11.015
[Indexed for MEDLINE]
Free PMC Article

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