Skip to main content

HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia.

Publication ,  Journal Article
Stewart, AS; Schaaf, CR; Luff, JA; Freund, JM; Becker, TC; Tufts, SR; Robertson, JB; Gonzalez, LM
Published in: Am J Physiol Gastrointest Liver Physiol
November 1, 2021

Intestinal ischemia is a life-threatening emergency with mortality rates of 50%-80% due to epithelial cell death and resultant barrier loss. Loss of the epithelial barrier occurs in conditions including intestinal volvulus and neonatal necrotizing enterocolitis. Survival depends on effective epithelial repair; crypt-based intestinal epithelial stem cells (ISCs) are the source of epithelial renewal in homeostasis and after injury. Two ISC populations have been described: 1) active ISC [aISC; highly proliferative; leucine-rich-repeat-containing G protein-coupled receptor 5 (LGR5+)-positive or sex-determining region Y-box 9 -antigen Ki67-positive (SOX9+Ki67+)] and 2) reserve ISC [rISC; less proliferative; homeodomain-only protein X positive (HOPX+)]. The contributions of these ISCs have been evaluated both in vivo and in vitro using a porcine model of mesenteric vascular occlusion to understand mechanisms that modulate ISC recovery responses following ischemic injury. In our previously published work, we observed that rISC conversion to an activated state was associated with decreased HOPX expression during in vitro recovery. In the present study, we wanted to evaluate the direct role of HOPX on cellular proliferation during recovery after injury. Our data demonstrated that during early in vivo recovery, injury-resistant HOPX+ cells maintain quiescence. Subsequent early regeneration within the intestinal crypt occurs around 2 days after injury, a period in which HOPX expression decreased. When HOPX was silenced in vitro, cellular proliferation of injured cells was promoted during recovery. This suggests that HOPX may serve a functional role in ISC-mediated regeneration after injury and could be a target to control ISC proliferation.NEW & NOTEWORTHY This paper supports that rISCs are resistant to ischemic injury and likely an important source of cellular renewal following near-complete epithelial loss. Furthermore, we have evidence that HOPX controls ISC activity state and may be a critical signaling pathway during ISC-mediated repair. Finally, we use multiple novel methods to evaluate ISCs in a translationally relevant large animal model of severe intestinal injury and provide evidence for the potential role of rISCs as therapeutic targets.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

November 1, 2021

Volume

321

Issue

5

Start / End Page

G588 / G602

Location

United States

Related Subject Headings

  • Tissue Culture Techniques
  • Sus scrofa
  • Stem Cells
  • Severity of Illness Index
  • Re-Epithelialization
  • Phenotype
  • Mesenteric Ischemia
  • Male
  • Intestinal Mucosa
  • Homeodomain Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Stewart, A. S., Schaaf, C. R., Luff, J. A., Freund, J. M., Becker, T. C., Tufts, S. R., … Gonzalez, L. M. (2021). HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia. Am J Physiol Gastrointest Liver Physiol, 321(5), G588–G602. https://doi.org/10.1152/ajpgi.00165.2021
Stewart, Amy Stieler, Cecilia Renee Schaaf, Jennifer A. Luff, John M. Freund, Thomas C. Becker, Sara R. Tufts, James B. Robertson, and Liara M. Gonzalez. “HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia.Am J Physiol Gastrointest Liver Physiol 321, no. 5 (November 1, 2021): G588–602. https://doi.org/10.1152/ajpgi.00165.2021.
Stewart AS, Schaaf CR, Luff JA, Freund JM, Becker TC, Tufts SR, et al. HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia. Am J Physiol Gastrointest Liver Physiol. 2021 Nov 1;321(5):G588–602.
Stewart, Amy Stieler, et al. “HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia.Am J Physiol Gastrointest Liver Physiol, vol. 321, no. 5, Nov. 2021, pp. G588–602. Pubmed, doi:10.1152/ajpgi.00165.2021.
Stewart AS, Schaaf CR, Luff JA, Freund JM, Becker TC, Tufts SR, Robertson JB, Gonzalez LM. HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia. Am J Physiol Gastrointest Liver Physiol. 2021 Nov 1;321(5):G588–G602.

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

November 1, 2021

Volume

321

Issue

5

Start / End Page

G588 / G602

Location

United States

Related Subject Headings

  • Tissue Culture Techniques
  • Sus scrofa
  • Stem Cells
  • Severity of Illness Index
  • Re-Epithelialization
  • Phenotype
  • Mesenteric Ischemia
  • Male
  • Intestinal Mucosa
  • Homeodomain Proteins