Epidermal Smad4 deletion results in aberrant wound healing.
In the present study, we assessed the role of Smad4, a component of the transforming growth factor-beta signaling pathway, in cutaneous wound repair. Interestingly, when Smad4 was deleted in the epidermis, several defects in wound healing were observed in non-keratinocyte compartments. In comparison with wounded wild-type mouse skin, Smad4-deficient wounds had delayed wound closure and remodeling. Increased angiogenesis and inflammation were found in Smad4-deficient skin; these effects were exacerbated throughout the entire wound healing process. In addition, increased numbers of myofibroblasts but reduced collagen levels were found in Smad4-deficient wounds in comparison with wild-type wounds. Since Smad4 is not a secreted protein, we assessed if the above non-cell autonomous alterations were the result of molecular alterations in Smad4-deficient keratinocytes, which exert paracrine effects on wound stroma. Smad4-deficient skin and wounds had elevated levels of transforming growth factor-beta1, which have been shown to induce similar phenotypes, as well as of several transforming growth factor-beta1 target genes, such as matrix metalloproteinases, vascular endothelial growth factor-A, and chemokine (C-C motif) ligand 5. Furthermore, the above pathological and molecular alterations were exacerbated in skin cancer lesions that spontaneously developed from Smad4-deficient skin. Therefore, loss of Smad4 in the epidermis appears to significantly affect the microenvironment during wound healing and carcinogenesis.
Owens
Philip
P
Department of Otolaryngology, Oregon Health Sciences University, Portland, Oregon, USA.
Engelking
Erin
E
Han
Gangwen
G
Haeger
Sarah M
SM
Wang
Xiao-Jing
XJ
D000015:Abnormalities, Multiple / Q000473:pathology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D004817:Epidermis / Q000002:abnormalities / Q000201:enzymology / Q000473:pathology*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009928:Organ Specificity; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D051901:Smad4 Protein / Q000172:deficiency* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing
D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases