Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy
Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy
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DOI：
10.1016/j.biomaterials.2018.04.055
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发表时间：
2018-08-01
期刊：
影响因子：
14
通讯作者：
Brodie, Chaya
中科院分区：
文献类型：
--
作者：
Bier, Ariel;Berenstein, Peter;Brodie, Chaya
杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的骨骼肌和心肌退行性致死性X连锁疾病。使用不同细胞类型的细胞治疗，包括间充质基质细胞（MSC），已被认为是治疗DMD的潜在方法。MSC可以从自体来源如骨髓和脂肪组织或从同种异体胎盘和脐带获得。这些细胞的安全性和治疗作用已在临床前和临床研究中得到证实，其功能归因于分泌的细胞因子和细胞外囊泡介导的旁分泌效应。在这里，我们使用来自健康对照、Duchenne患者和mdx小鼠的小鼠和人成肌细胞研究了胎盘来源的MSC（PL-MSC）及其分泌的外泌体的治疗作用。用PL-MSC分泌的条件培养基或外泌体处理成肌细胞增加了这些细胞的分化，并降低了DMD患者成肌细胞中纤维化基因的表达。此外，这些处理还增加了这些细胞中utrophin的表达。使用定量miR-29 c报告基因，我们证明PL-MSC效应部分由外泌体miR-29 c的转移介导。骨髓间充质干细胞肌内移植mdx小鼠导致肌酸激酶水平下降。PL-MSCs显著降低了TGF-β的表达和膈肌和心肌纤维化的水平，抑制炎症并增加utrophin的表达。使用金纳米颗粒或荧光染料标记的MSC进行的体内成像分析表明，治疗后3周内细胞在肌肉组织中的定位。总之，这些结果表明，PL-MSC及其分泌的外泌体在DMD的细胞治疗中具有重要的临床应用，部分地通过外泌体miR-29 c的靶向递送。(C)2018由Elsevier Ltd.出版
Duchenne muscular dystrophy (DMD) is a degenerative lethal, X-linked disease of skeletal and cardiac muscles caused by mutations in the dystrophin gene. Cell therapy using different cell types, including mesenchymal stromal cells (MSCs), has been considered as a potential approach for the treatment of DMD. MSCs can be obtained from autologous sources such as bone marrow and adipose tissues or from allogeneic placenta and umbilical cord. The safety and therapeutic impact of these cells has been demonstrated in pre-clinical and clinical studies and their functions are attributed to paracrine effects that are mediated by secreted cytokines and extracellular vesicles. Here, we studied the therapeutic effects of placenta-derived MSCs (PL-MSCs) and their secreted exosomes using mouse and human myoblasts from healthy controls, Duchenne patients and mdx mice. Treatment of myoblasts with conditioned medium or exosomes secreted by PL-MSCs increased the differentiation of these cells and decreased the expression of fibrogenic genes in DMD patient myoblasts. In addition, these treatments also increased the expression of utrophin in these cells. Using a quantitative miR-29c reporter, we demonstrated that the PL-MSC effects were partly mediated by the transfer of exosomal miR-29c. Intramuscular transplantation of PL-MSCs in mdx mice resulted in decreased creatine kinase levels. PL-MSCs significantly decreased the expression of TGF-beta and the level of fibrosis in the diaphragm and cardiac muscles, inhibited inflammation and increased utrophin expression. In vivo imaging analyses using MSCs labeled with gold nanoparticles or fluorescent dyes demonstrated localization of the cells in the muscle tissues up to 3 weeks post treatment. Altogether, these results demonstrate that PL-MSCs and their secreted exosomes have important clinical applications in cell therapy of DMD partly via the targeted delivery of exosomal miR-29c. (C) 2018 Published by Elsevier Ltd.