Early but not late administration of glucagon-like peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion

University of North Carolina at Chapel Hill, Department of Surgery, G140 Physician's Office Bldg., CB #7223, Chapel Hill, NC 27599-7223, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 01/2009; 296(3):G643-50. DOI: 10.1152/ajpgi.90588.2008
Source: PubMed

ABSTRACT Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated beta-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.

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    • "Post-ICR samples were collected at 7, 14 and 28 days following surgery as indicated. We selected day 7 after ICR because at this time point we have previously reported that the expansion of crypts that contribute to long term adaptation is initiated along with acute changes in proliferation and crypt depth and villus height [24,27,42]. At later time points of 14 and 28 days, the acute increases in proliferation, crypt depth and villus height are decreasing whereas sustained increases in the overall number of jenunal cypts persist [24]. "
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