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Title: Rhamm-/- mice are defective in skin wound repair due to aberrantERK1,2 signaling in fibroblast migration

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
COLLABORATION - Cancer ResearchLaboratories/Canada
Sponsoring Org.:
USDOE Director. Office of Science. Biological andEnvironmental Research
OSTI Identifier:
920151
Report Number(s):
LBNL-59977
R&D Project: 443180; BnR: KP1104010
DOE Contract Number:
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Cell Biology; Journal Volume: 175; Journal Issue: 6; Related Information: Journal Publication Date: 12/18/2006
Country of Publication:
United States
Language:
English
Subject:
60

Citation Formats

Tolg, Cornelia, Hamilton, Sara R., Kooshesh, Pari, McCarthy,James B., Bissell, Mina J., and Turley, Eva A. Rhamm-/- mice are defective in skin wound repair due to aberrantERK1,2 signaling in fibroblast migration. United States: N. p., 2006. Web. doi:10.1083/jcb.200511027.
Tolg, Cornelia, Hamilton, Sara R., Kooshesh, Pari, McCarthy,James B., Bissell, Mina J., & Turley, Eva A. Rhamm-/- mice are defective in skin wound repair due to aberrantERK1,2 signaling in fibroblast migration. United States. doi:10.1083/jcb.200511027.
Tolg, Cornelia, Hamilton, Sara R., Kooshesh, Pari, McCarthy,James B., Bissell, Mina J., and Turley, Eva A. Mon . "Rhamm-/- mice are defective in skin wound repair due to aberrantERK1,2 signaling in fibroblast migration". United States. doi:10.1083/jcb.200511027. https://www.osti.gov/servlets/purl/920151.
@article{osti_920151,
title = {Rhamm-/- mice are defective in skin wound repair due to aberrantERK1,2 signaling in fibroblast migration},
author = {Tolg, Cornelia and Hamilton, Sara R. and Kooshesh, Pari and McCarthy,James B. and Bissell, Mina J. and Turley, Eva A.},
abstractNote = {},
doi = {10.1083/jcb.200511027},
journal = {Journal of Cell Biology},
number = 6,
volume = 175,
place = {United States},
year = {Mon Apr 03 00:00:00 EDT 2006},
month = {Mon Apr 03 00:00:00 EDT 2006}
}
  • Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up-regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Westernmore » blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-β-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of β-catenin, suggesting that β-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy. - Highlights: • bFGF regulates Hedgehog (Hh) signaling in fibroblasts. • The Smo and Gli two master regulators of Hh signaling positively regulate fibroblast migration. • Smo facilitates β-catenin nuclear translocation via activation PI3K/JNK/GSK3β. • β-catenin positively regulates fibroblast cell migration and the expression of Hh signaling genes including Smo and Gli.« less
  • We have used in vitro scratch assays to examine the relative contribution of dermal fibroblasts and keratinocytes in the wound repair process and to test the influence of mesenchymal stem cell (MSC) secreted factors on both skin cell types. Scratch assays were established using single cell and co-cultures of L929 fibroblasts and HaCaT keratinocytes, with wound closure monitored via time-lapse microscopy. Both in serum supplemented and serum free conditions, wound closure was faster in L929 fibroblast than HaCaT keratinocyte scratch assays, and in co-culture the L929 fibroblasts lead the way in closing the scratches. MSC-CM generated under serum free conditionsmore » significantly enhanced the wound closure rate of both skin cell types separately and in co-culture, whereas conditioned medium from L929 or HaCaT cultures had no significant effect. This enhancement of wound closure in the presence of MSC-CM was due to accelerated cell migration rather than increased cell proliferation. A number of wound healing mediators were identified in MSC-CM, including TGF-{beta}1, the chemokines IL-6, IL-8, MCP-1 and RANTES, and collagen type I, fibronectin, SPARC and IGFBP-7. This study suggests that the trophic activity of MSC may play a role in skin wound closure by affecting both dermal fibroblast and keratinocyte migration, along with a contribution to the formation of extracellular matrix.« less
  • Chemoattractant activity for irradiated and nonirradiated rabbit skin fibroblast and bovine aortic arch endothelial cells was assayed in rabbit wound fluid and sera using a modification of the agarose well method originally described for polymorphonuclear leukocytes. Both serum and wound fluid contained chemoattractants for fibroblasts and endothelial cells. Fibroblast migration was decreased by 70 to 80% when the serum or wound fluid was heated to 56 degrees C for 30 min while endothelial cell migration was reduced by 50 to 60%. Platelet-poor plasma-derived serum had no directive effect on the migration of either cell type.
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