Wu Yan, Huang Sha, Enhe Jirigala, Ma Kui, Yang Siming, Sun Tongzhu, Fu Xiaobing
The Institute of Basic Medical Sciences, Chinese PLA General Hospital, Beijing, China; School of Medicine, Nankai University, Tianjin, China; Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, China; Burns Institute, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China.
Int Wound J. 2014 Dec;11(6):701-10. doi: 10.1111/iwj.12034. Epub 2013 Feb 15.
Recent studies showed that mesenchymal stem cell (MSC) transplantation significantly alleviated tissue fibrosis; however, little is known about the efficacy on attenuating cutaneous scar formation. In this study, we established a dermal fibrosis model induced by bleomycin and evaluated the benefit of bone marrow-derived mesenchymal stem cells (BM-MSCs) on skin fibrosis development. Tracing assay of green fluorescent protein (GFP(+) )BM-MSCs showed that the cells disappeared gradually within 24 hours upon administration, which hinted the action of BM-MSCs in vivo was exerted in the initial phase of repair in this model. Therefore, we repeatedly transplanted syngeneic BM-MSCs in the process of skin fibrosis formation. After 3 weeks, it was found that BM-MSC-treated lesional skin demonstrated a unanimous basket-weave organisation of collagen arrangement similar to normal skin, with few inflammatory cells. In addition, lesional skin with BM-MSC treatment exhibited a significant down-regulation of transforming growth factor-β1 (TGF-β1), type I collagen and heat-shock protein 47 (HSP47), with higher expression of matrix metalloproteinases (MMPs)-2, -9 and -13. Further experiments showed that α-smooth muscle actin (α-SMA) positive cells, the most reliable marker of myofibroblasts, apparently decreased after BM-MSC transplantation, which revealed that BM-MSCs could attenuate myofibroblast proliferation and differentiation as well as matrix production. Taken together, these findings suggested that BM-MSCs can inhibit the formation process of bleomycin-induced skin fibrosis, alleviate inflammation and favour the remodelling of extracellular matrix.
近期研究表明，间充质干细胞（MSC）移植可显著减轻组织纤维化；然而，其对减轻皮肤瘢痕形成的效果却鲜为人知。在本研究中，我们建立了博来霉素诱导的真皮纤维化模型，并评估了骨髓间充质干细胞（BM-MSCs）对皮肤纤维化发展的作用。绿色荧光蛋白（GFP(+)）BM-MSCs的示踪分析表明，给药后24小时内细胞逐渐消失，这提示在该模型中BM-MSCs在体内的作用是在修复的初始阶段发挥的。因此，我们在皮肤纤维化形成过程中反复移植同基因BM-MSCs。3周后，发现经BM-MSCs处理的皮损皮肤呈现出与正常皮肤相似的一致的胶原排列篮状结构，炎症细胞较少。此外，经BM-MSCs处理的皮损皮肤中转化生长因子-β1（TGF-β1）、I型胶原和热休克蛋白47（HSP47）表达显著下调，而基质金属蛋白酶（MMPs）-2、-9和-13的表达较高。进一步实验表明，α-平滑肌肌动蛋白（α-SMA）阳性细胞（成肌纤维细胞最可靠的标志物）在BM-MSCs移植后明显减少，这表明BM-MSCs可减弱成肌纤维细胞的增殖和分化以及基质产生。综上所述，这些发现提示BM-MSCs可抑制博来霉素诱导的皮肤纤维化形成过程，减轻炎症并促进细胞外基质重塑。
