Wu Yan, Peng Yan, Gao Dongyun, Feng Changjiang, Yuan Xiaohuan, Li Houzhong, Wang Ying, Yang Lan, Huang Sha, Fu Xiaobing
Mudanjiang Medical College, Mudanjiang, People's Republic of China The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China General Hospital of PLA, Beijing, People's Republic of China.
The University of Hong Kong, Hong Kong SAR, People's Republic of China.
Int J Low Extrem Wounds. 2015 Mar;14(1):50-62. doi: 10.1177/1534734614568373.
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-β (TGF-β)-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-β3 secreted by MSCs was expressed at high level under inflammatory environment, and blocking the activity of TGF-β3 apparently antagonized the suppressive activity of MSC CM, which demonstrated that TGF-β3 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 α-smooth muscle actin revealed that TGF-β3 of CM-mediated therapeutic effects could obviously attenuate matrix production and myofibroblast proliferation and differentiation. These findings suggest that TGF-β3 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.
最近的研究表明，间充质干细胞（MSC）移植可显著降低组织纤维化；然而，其对减轻皮肤纤维化的功效鲜受关注，且对其作用机制了解甚少。在本研究中，我们通过旁分泌作用研究了MSC对瘢痕疙瘩成纤维细胞和细胞外基质沉积的影响，以及MSC的抗纤维化特性是否涉及转化生长因子-β（TGF-β）依赖性激活。体外实验表明，MSC的条件培养基（CM）可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蛋白分泌。此外，MSC分泌的TGF-β3在炎症环境下高表达，阻断TGF-β3的活性明显拮抗了MSC CM的抑制活性，这表明TGF-β3在预防胶原蛋白积累中起主要作用。体内研究表明，在小鼠皮肤纤维化模型中输注MSC CM可显著降低皮肤纤维化。组织切片的组织学检查和α平滑肌肌动蛋白的免疫组化分析显示，CM介导的治疗作用中的TGF-β3可明显减弱基质产生以及肌成纤维细胞的增殖和分化。这些发现表明，TGF-β3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减弱作用，并降低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。
