Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway

Abstract

BackgroundHypertrophic scars (HS) generally occur after injury to the deep layers of the dermis, resulting in functional deficiency for patients. Growing evidence has been identified that the supernatant of adipose tissue-derived stem cells (ADSCs) significantly ameliorates fibrosis of different tissues, but limited attention has been paid to its efficacy on attenuating skin fibrosis. In this study, we explored the effect and possible mechanism of ADSC-conditioned medium (ADSC-CM) on HS.MethodReal-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of collagen I (Col1), collagen III (Col3), and α-smooth muscle actin (α-SMA) after fibroblasts and cultured HS tissues were stimulated with ADSC-CM and p38 inhibitor/activator. Immunofluorescence staining was performed to test the expression of α-SMA. Masson’s trichrome staining, hematoxylin and eosin (H&E) staining, and immunohistochemistry staining were carried out to assess the histological and pathological change of collagen in the BALB/c mouse excisional model. All data were analyzed by using SPSS17.0 software. Statistical analysis was performed by Student’s t tests.ResultsThe in vitro and ex vivo study revealed ADSC-CM decreased the expression of Col1, Col3, and α-SMA. Together, thinner and orderly arranged collagen was manifested in HS tissues cultured with ADSC-CM. Dramatically, the assessed morphology showed an accelerated healing rate, less collagen deposition, and col1- and col3-positive cells in the ADSC-CM treated group. Importantly, the protein level of p-p38 was downregulated in a concentration-dependent manner in HS-derived fibroblasts with ADSC-CM treatment, which further decreased the expression of p-p38 after the application of its inhibitor, SB203580. SB203580 led to an obvious decline in the expression of Col1, Col3, and α-SMA in fibroblasts and cultured HS tissues and presented more ordered arrangement and thinner collagen fibers in BALB/c mice. Lastly, anisomycin, an agonist of p38, upregulated the expression of fibrotic proteins and revealed more disordered structure and denser collagen fibers.ConclusionThis study demonstrated that ADSC-CM could decrease collagen deposition and scar formation in in vitro, ex vivo and in vivo experiments. The regulation of the p38/MAPK signaling pathway played an important role in the process. The application of ADSC-CM may provide a novel therapeutic strategy for HS treatment, and the anti-scarring effect can be achieved by inhibition of the p38/MAPK signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0356-6) contains supplementary material, which is available to authorized users.

Prospective application of stem cells to prevent post‐operative skeletal fibrosis

“…Skin fibrosis is a pathological outcome of various injuries including wound injuries, exogenous‐induced fibrosis and autoimmune skin diseases. There are three fibrosis models, including bleomycin‐induced fibrosis, radiation‐induced fibrosis and excisional‐induced fibrosis . These models are used to detect the effect of stem cells on skin fibrosis.…”

“…In addition to the above mentioned mechanisms, others include the p38/MAPK pathway, regulation of miR‐let7c and the ER stress pathway . In particular, ER stress has been proven to be linked to post‐operative skeletal fibrosis .…”

“…There are three fibrosis models, including bleomycin-induced fibrosis, 9,128 radiation-induced fibrosis [129][130][131] and excisional-induced fibrosis. 132,133 These models are used to detect the effect of stem cells on skin fibrosis. Results have revealed that stem cells could reduce skin fibrosis and promote skin healing by decreasing collagen deposition, 9,133 suppressing macrophage and neutrophil infiltration, 9,130 inhibiting expression levels of TGF-b1, 9,128,129,133 IL-1, 130 VEGF, 128 a-SMA 9,133 and TNF-a 130,133 and increasing expression levels of MMPs 9 and IL-10.…”

Adipose‐derived stem cells for wound healing

“…, and activation of fibroblasts per se may lead to disorganised fibroblast depositions and scar formation(Bainbridge, 2013), attenuation of scar formation following the ASCs therapy might occur due to the effect of ASCs on the function of fibroblasts. With this regard, preclinical studies showed that ASC-conditioned medium decreased collagen deposition and expression of α-smooth muscle actin in hypertrophic scar fibroblasts, resulting in attenuation of scarring (Y Li et al, 2016)…”

The Specific Features of Tissue Reaction after Vein Ligation in Experiment

“…Культуральная среда после выращивания МСК жировой ткани подавляет фибротические процессы в глубоких слоях кожи, уменьшаются объем коллагена и формирование рубцовой ткани [2]. МСК пуповинной крови человека снижают выраженность развития соединительной ткани и портальной гипертензии при индуцированном фиброзе печени у мышей и крыс [3,4].…”