Mesenchymal Stem Cells Suppress Fibroblast Proliferation and Reduce Skin Fibrosis Through a TGF-β3-Dependent Activation
Mesenchymal Stem Cells Suppress Fibroblast Proliferation and Reduce Skin Fibrosis Through a TGF-β3-Dependent Activation
复制标题
间充质干细胞通过 TGF-β 3 依赖性激活抑制成纤维细胞增殖并减少皮肤纤维化
DOI：
10.1177/1534734614568373
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发表时间：
2015-03-01
影响因子：
1.7
通讯作者：
Fu, Xiaobing
中科院分区：
文献类型：
--
作者：
Wu, Yan;Peng, Yan;Fu, Xiaobing
最近的研究表明，间充质干细胞（MSCs）的移植显着减少组织纤维化，但很少有人注意到它对减轻皮肤纤维化的疗效，其作用机制知之甚少。在这项工作中，我们研究了骨髓间充质干细胞对瘢痕疙瘩成纤维细胞和细胞外基质沉积的影响，通过旁分泌行动，以及是否骨髓间充质干细胞的抗纤维化特性涉及转化生长因子-β（TGF-β）依赖性激活。体外实验表明，来自MSC的条件培养基（CM）降低人瘢痕疙瘩成纤维细胞的活力、α-平滑肌肌动蛋白表达和胶原分泌。此外，MSC分泌的TGF-β 3在炎症环境中高水平表达，阻断TGF-β 3的活性可明显拮抗MSC CM的抑制活性，表明TGF-β 3在阻止胶原积聚方面发挥了优势作用。体内研究表明，MSC CM输注在小鼠皮肤纤维化模型中诱导皮肤纤维化的显著减少。组织切片的组织学检查和平滑肌肌动蛋白的免疫组化分析显示，CM介导的治疗作用的TGF-β 3可以明显减弱基质产生和肌成纤维细胞增殖和分化。这些结果表明TGF-β 3介导了MSC对人瘢痕疙瘩成纤维细胞增殖和细胞外基质产生的抑制作用，并减轻了小鼠模型的皮肤纤维化，从而为皮肤瘢痕治疗提供了新的认识和基于MSC的治疗策略。
Recent studies showed that transplantation of mesenchymal stem cells (MSCs) significantly decreased tissue fibrosis; however, little attention has been paid to its efficacy on attenuating skin fibrosis, and the mechanism involved in its effect is poorly understood. In this work, we investigated the effects of MSCs on keloid fibroblasts and extracellular matrix deposition through paracrine actions and whether the antifibrotic properties of MSCs involved transforming growth factor-beta (TGF-beta)-dependent activation. In vitro experiments showed that conditioned media (CM) from MSCs decreased viability, a-smooth muscle actin expression, and collagen secretion of human keloid fibroblasts. In addition, TGF-beta 3 secreted by MSCs was expressed at high level under inflammatory environment, and blocking the activity of TGF-beta 3 apparently antagonized the suppressive activity of MSC CM, which demonstrated that TGF-beta 3 played a preponderant role in preventing collagen accumulation. In vivo studies showed that MSC CM infusion in a mouse dermal fibrosis model induced a significant decrease in skin fibrosis. Histological examination of tissue sections and immunohistochemical analysis for -smooth muscle actin revealed that TGF-beta 3 of CM-mediated therapeutic effects could obviously attenuate matrix production and myofibroblast proliferation and differentiation. These findings suggest that TGF-beta 3 mediates the attenuating effect of MSCs on both the proliferation and extracellular matrix production of human keloid fibroblasts and decreases skin fibrosis of mouse model, thus providing new understanding and MSC-based therapeutic strategy for cutaneous scar treatment.