Distraction-induced intestinal growth: the role of mechanotransduction mechanisms in a mouse model of short bowel syndrome.
Novel strategies are needed to address the problem of patients with short bowel syndrome. We previously demonstrated a three-fold lengthening of pig bowel after 2 weeks of applied distractive forces, but we have not elucidated the mechanisms facilitating this growth. We used a mouse model of distraction-induced enterogenesis. High molecular weight polyethylene glycol (PEG) osmotically stretched an isolated small bowel segment (PEG-stretch). Significant increases in villus height and crypt depth and in intestinal epithelial cell length and numbers suggested epithelial remodeling in addition to proliferation during enterogenesis. LC-MS/MS analysis showed a two-fold upregulation of α-actinin-1 and -4. We also demonstrated that p-focal adhesion kinase (FAK), FAK, α-actinin, and Rac1 were significantly upregulated and that F-actin was relocalized in PEG-stretch versus controls. Blockade of the phosphotidyl inositol 3' kinase pathway failed to influence the increase in proliferation or decline in apoptosis after stretch, suggesting alternative signaling pathways are used, including MEK and P38MAPK, which were both upregulated during enterogenesis. Our data suggests that several known mechanotransduction pathways drive distraction-induced enterogenesis.
Section of Pediatric Surgery, Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
Ryo
R
Sueyoshi
Kathleen M
KM
Woods Ignatoski
Manabu
M
Okawada
Daniel H
DH
Teitelbaum
D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D013058:Mass Spectrometry; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012778:Short Bowel Syndrome / Q000378:metabolism* / Q000473:pathology*; D034421:Sus scrofa; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D012333:RNA, Messenger; D000185:Actinin; D011092:Polyethylene Glycols; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020830:rac1 GTP-Binding Protein