Akt-mediated mechanotransduction in murine fibroblasts during hypertrophic scar formation.
Although numerous factors are implicated in skin fibrosis, the exact pathophysiology of hypertrophic scarring remains unknown. We recently demonstrated that mechanical force initiates hypertrophic scar formation in a murine model, potentially enhancing cellular survival through Akt. Here, we specifically examined Akt-mediated mechanotransduction in fibroblasts using both strain culture systems and our murine scar model. In vitro, static strain increased fibroblast motility, an effect blocked by wortmannin (a phosphoinositide-3-kinase/Akt inhibitor). We also demonstrated that high-frequency cyclic strain was more effective at inducing Akt phosphorylation than low frequency or static strain. In vivo, Akt phosphorylation was induced by mechanical loading of dermal fibroblasts in both unwounded and wounded murine skin. Mechanically loaded scars also exhibited strong expression of α-smooth muscle actin, a putative marker of pathologic scar formation. In vivo inhibition of Akt increased apoptosis but did not significantly abrogate hypertrophic scar development. These data suggest that although Akt signaling is activated in fibroblasts during mechanical loading of skin, this is not the critical pathway in hypertrophic scar formation. Future studies are needed to fully elucidate the critical mechanotransduction components and pathways which activate skin fibrosis.
Department of Surgery, School of Medicine, Stanford University, Stanford, California 94305, USA.
Josemaria
J
Paterno
Ivan N
IN
Vial
Victor W
VW
Wong
Kristine C
KC
Rustad
Michael
M
Sorkin
Yubin
Y
Shi
Kirit A
KA
Bhatt
Hariharan
H
Thangarajah
Jason P
JP
Glotzbach
Geoffrey C
GC
Gurtner
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement; D002470:Cell Survival; D017439:Cicatrix, Hypertrophic / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D005347:Fibroblasts / Q000502:physiology*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D013314:Stress, Mechanical; D000077191:Wortmannin
D000730:Androstadienes; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin