Dermal transforming growth factor-beta responsiveness mediates wound contraction and epithelial closure.
Submitted by Magaly Martinez-Ferrer on
Title | Dermal transforming growth factor-beta responsiveness mediates wound contraction and epithelial closure. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Martinez-Ferrer, M, Afshar-Sherif, A-R, Uwamariya, C, de Crombrugghe, B, Davidson, JM, Bhowmick, NA |
Journal | Am J Pathol |
Volume | 176 |
Issue | 1 |
Pagination | 98-107 |
Date Published | 2010 Jan |
ISSN | 1525-2191 |
Keywords | Actins, Animals, Cytoskeleton, Dermis, Epithelium, Extracellular Matrix, Granulation Tissue, Inflammation, Integrases, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Recombination, Genetic, Signal Transduction, Transforming Growth Factor beta, Wound Healing |
Abstract | Stromal-epithelial interactions are important during wound healing. Transforming growth factor-beta (TGF-beta) signaling at the wound site has been implicated in re-epithelization, inflammatory infiltration, wound contraction, and extracellular matrix deposition and remodeling. Ultimately, TGF-beta is central to dermal scarring. Because scarless embryonic wounds are associated with the lack of dermal TGF-beta signaling, we studied the role of TGF-beta signaling specifically in dermal fibroblasts through the development of a novel, inducible, conditional, and fibroblastic TGF-beta type II receptor knockout (Tgfbr2(dermalKO)) mouse model. Full thickness excisional wounds were studied in control and Tgfbr2(dermalKO) back skin. The Tgfbr2(dermalKO) wounds had accelerated re-epithelization and closure compared with controls, resurfacing within 4 days of healing. The loss of TGF-beta signaling in the dermis resulted in reduced collagen deposition and remodeling associated with a reduced extent of wound contraction and elevated macrophage infiltration. Tgfbr2(dermalKO) and control skin had similar numbers of myofibroblastic cells, suggesting that myofibroblastic differentiation was not responsible for reduced wound contraction. However, several mediators of cell-matrix interaction were reduced in the Tgfbr2(dermalKO) fibroblasts, including alpha1, alpha2, and beta1 integrins, and collagen gel contraction was diminished. There were associated deficiencies in actin cytoskeletal organization of vasodilator-stimulated phosphoprotein-containing lamellipodia. This study indicated that paracrine and autocrine TGF-beta dermal signaling mechanisms mediate macrophage recruitment, re-epithelization, and wound contraction. |
DOI | 10.2353/ajpath.2010.090283 |
Alternate Journal | Am. J. Pathol. |
PubMed ID | 19959810 |
PubMed Central ID | PMC2797873 |
Grant List | AG06528 / AG / NIA NIH HHS / United States CA108646 / CA / NCI NIH HHS / United States CA68485 / CA / NCI NIH HHS / United States DK069527 / DK / NIDDK NIH HHS / United States DK20593 / DK / NIDDK NIH HHS / United States DK58404 / DK / NIDDK NIH HHS / United States DK59637 / DK / NIDDK NIH HHS / United States EY08126 / EY / NEI NIH HHS / United States HD15052 / HD / NICHD NIH HHS / United States R01 AG006528 / AG / NIA NIH HHS / United States |