Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice
Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice
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DOI：
10.1172/jci.insight.125754
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发表时间：
2019-04-04
期刊：
影响因子：
8
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
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作者：
Rogers, Russell G.;Fournier, Mario;Marban, Eduardo
在Duchenne肌营养不良症(DMD)患者中，营养不良蛋白缺乏会导致进行性肌肉退化。目前还没有已知的治愈方法，标准护理依赖于抗炎类固醇的使用，这与副作用有关，使长期使用复杂化。在这里，我们报告了单次静脉注射临床阶段的心脏基质细胞，称为心球源性细胞(CDCs)，改善了MDX小鼠的营养不良表型。CDCs增强心肌和骨骼肌功能，部分逆转已建立的心肌损伤，并增强骨骼肌的再生能力。我们进一步证明，CDC通过分泌外体来工作，外体在转录组水平上使基因表达正常化，并改变MDX心脏和骨骼肌中的细胞信号和生物过程。本文报道的工作激励了正在进行的系统性CDC给DMD患者的HOPE-2临床试验，并确定外切体是DMD的下一代无细胞治疗候选者。
Dystrophin deficiency leads to progressive muscle degeneration in Duchenne muscular dystrophy (DMD) patients. No known cure exists, and standard care relies on the use of antiinflammatory steroids, which are associated with side effects that complicate long-term use. Here, we report that a single intravenous dose of clinical-stage cardiac stromal cells, called cardiosphere-derived cells (CDCs), improves the dystrophic phenotype in mdx mice. CDCs augment cardiac and skeletal muscle function, partially reverse established heart damage, and boost the regenerative capacity of skeletal muscle. We further demonstrate that CDCs work by secreting exosomes, which normalize gene expression at the transcriptome level, and alter cell signaling and biological processes in mdx hearts and skeletal muscle. The work reported here motivated the ongoing HOPE-2 clinical trial of systemic CDC delivery to DMD patients, and identifies exosomes as next-generation cell-free therapeutic candidates for DMD.