Dermal transforming growth factor-beta responsiveness mediates wound contraction and epithelial closure.
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.
Martinez-Ferrer
Magaly
M
Vanderbilt-Ingram Cancer Center and Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Afshar-Sherif
Ali-Reza
AR
Uwamariya
Consolate
C
de Crombrugghe
Benoit
B
Davidson
Jeffrey M
JM
Bhowmick
Neil A
NA
D000199:Actins / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D020405:Dermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D000199:Actins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C045073:Cre recombinase; D019426:Integrases