Submitted on October 8, 2008
Revised on December 22, 2008
Accepted on December 27, 2008
Early but not late administration of Glucagon-Like Peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion
Aaron Paul Garrison1, Christopher M. Dekaney2, Douglas Clayton von Allmen1, Pauline Kay Lund1, Susan June Henning3, and Michael Anthony Helmrath1*
1 University of North Carolina, Chapel Hill
2 University of North Carolina at Chapel Hill
3 University of North Carolina
* To whom correspondence should be addressed. E-mail: michael_helmrath{at}med.unc.edu.
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 GLP-2 would augment jejunal pISC expansion only when administered to mice immediately after ICR. As recent reports demonstrated increases in intestinal 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 prior to tissue harvest 6 weeks 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 (FACS) of side population (SP) cells, immunohistochemistry for phosphorylated 
-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.
