Early but not late administration of glucagon-like peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion.
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.
Garrison
Aaron P
AP
University of North Carolina at Chapel Hill, Department of Surgery, G140 Physician's Office Bldg., CB #7223, Chapel Hill, NC 27599-7223, USA.
Dekaney
Christopher M
CM
von Allmen
Douglas C
DC
Lund
P Kay
PK
Henning
Susan J
SJ
Helmrath
Michael A
MA
D000818:Animals; D002432:Cecum / Q000473:pathology* / Q000601:surgery; D002455:Cell Division / Q000187:drug effects; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism / Q000494:pharmacology*; D007082:Ileum / Q000473:pathology* / Q000601:surgery; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007410:Intestinal Diseases / Q000473:pathology / Q000601:surgery*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D011183:Postoperative Complications / Q000188:drug therapy* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D053767:Glucagon-Like Peptide 2; D011506:Proteins; D051176:beta Catenin; C475853:serin-rich spermatogenic protein 1, rat; D007334:Insulin-Like Growth Factor I