杜氏肌营养不良症（DMD）是最常见的遗传性致死性肌肉疾病，目前尚无有效治疗方法。骨髓间充质干细胞（MSC）移植治疗DMD是富有前景的手段之一，然而存在两大阻碍：晚期患者骨骼肌的纤维化屏障和MSC骨骼肌重建效率（增殖、存活、成肌分化和成血管）欠佳。研究表明，基质金属蛋白酶1（MMP-1）不仅对各组织有明显的抗纤维化作用，且能促进肌肉干细胞迁移和成肌分化。我们发现MMP-1对MSC成肌分化亦有显著促进作用，且无细胞毒性。那么，能否进一步将MMP-1安全有效地用于MSC移植治疗DMD？本项目拟采用Tet-on系统、慢病毒转导技术构建可诱导高表达MMP-1的MSC（MMP-1-MSC），同时用shRNA技术下调MMP-1表达作为对照，通过细胞培养、mdx小鼠（DMD模型鼠）注射的方法，从正反两方面、体内体外两个角度探讨MMP-1-MSC改善骨骼肌纤维化和重建效率的作用，为DMD临床治疗提供新思路。

Duchenne's muscular dystrophy (DMD), one of the most common hereditary diseases, is a fatal muscular disorder with no effective treatments available currently. Mesenchymal stem cell (MSC) proved to be a promising candidate for future cell-therapy protocol in DMD patients. Fibrosis, characterized advanced stages of DMD, however, may impede muscle regeneration by posing as a mechanical barrier to MSC migration and fusion and reducing potential of muscular differentiation. It is reported that matrix metalloproteinase-1 (MMP-1) can reduce collagen deposition in tissues and promote muscle regeneration by improving myoblast migration and differentiation. Our previous study encouragingly demonstrated that MMP-1, in vitro, can enhance myogenic differentiation of MSC without cytotoxic effects. The goal of this study is to further investigate whether modified MSC induced to overexpress MMP-1 (MSC/MMP-1-up), while not MSC infected of shRNA targeting MMP-1 (MSC/MMP-1-dn), may overcome the fibrosis barrier and benefit muscle regeneration both in vitro and in aged mdx mice (an animal model for DMD). A Tet-On System with 4th Generation Lentiviral Packaging System may be used to construct MMP-1-MSC. We suppose that MSC modified by MMP-1 will provide a novel and promising therapeutic approach for DMD.