Abstract
IntroductionMesenchymal stem cells (MSCs) are considered to play important roles in wound repair and tissue remodeling. Hypertrophic scar (HTS) is a cutaneous condition characterized by deposits of excessive amount of collagen after an acute skin injury. However, currently there is little knowledge about the direct relationship between MSCs and HTS.MethodsThe hypertrophic scar model was established on rabbit ears. MSCs were isolated from rabbit femur bone marrow and transplanted through ear artery injection. Hypertrophic scar formation was examined using frozen-section analysis, hematoxylin and eosin (HE) staining, Masson’s trichrome staining, and scar elevation index. The role of p53 in the MSCs-mediated anti-scarring effect was examined by gene knockdown using p53 shRNA.ResultsIn this study, MSCs engraftment through ear artery injection significantly inhibited the hypertrophic scarring in a rabbit ear hypertrophic scar model, while this anti-scarring function could be abrogated by p53 gene knockdown in MSCs. Additionally, we found that MSCs down-regulated the expression of TGF-β receptor I (TβRI) and alpha-smooth muscle actin (α-SMA) at both mRNA and protein levels in a paracrine manner, and this down-regulation was rescued by p53 gene knockdown. Moreover, our results showed that MSCs with p53 gene knockdown promoted the proliferation of fibroblasts through increasing nitric oxide (NO) production.ConclusionsThese results suggest that MSCs inhibit the formation of HTS in a p53 dependent manner through at least two mechanisms: inhibition of the transformation of HTS fibroblast to myofibroblast; and inhibition of the proliferation of fibroblasts through inhibition of NO production.
Highlights
Mesenchymal stem cells (MSCs) are considered to play important roles in wound repair and tissue remodeling
Both kinds of cells would differentiate into mineralizing cells stained by alizarin red after osteogenic induction or adipocytes stained by oil red after adipogenic induction (Figure 1H). These results suggested that p53 shRNA-transduced and control shRNA-transduced MSCs maintained the common features of MSCs
We found that conditioned medium from control shRNA-transduced MSCs significantly downregulated TGF-β receptor I (TβRI) and alpha-smooth muscle actin (α-SMA) in both mRNA (Figure 4A) and protein (Figure 4B,C) levels, while the conditioned medium from p53 shRNAtransduced MSCs did not affect the expression of TβRI and α-SMA
Summary
Mesenchymal stem cells (MSCs) are considered to play important roles in wound repair and tissue remodeling. Hypertrophic scar (HTS) is a common complication of burn injury and other soft tissue injuries. HTS is characterized by the proliferation of a large number of fibroblasts, accumulation of collagen and infiltration of inflammatory cells [3]. Apart from the fibroblasts that have been recognized as one of the driving factors of HTS, mesenchymal stem cells (MSCs) were found to have multiple functions in the formation of HTS [3,4,5]. MSCs are multipotent cells that can migrate to the wound sites, where they form part of the microenvironment [6,7,8], improve wound healing and inhibit hypertrophic scarring [9,10,11]. The mechanisms of the anti-scarring function of MSCs and the interaction between MSCs and HTS fibroblast remain poorly understood
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