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 andin vitrousing 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 HOPXexpression during in vitrorecovery. In the present study, we wished to evaluate the direct role of HOPXon 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 post 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 HOPXmay serve a functional role in ISC mediated regeneration after injury and could be a target to control ISC proliferation.
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