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Exosome-Mediated Benefits of Cell Therapy in Mouse and Human Models of Duchenne Muscular Dystrophy

机译：在小鼠和杜兴氏肌营养不良症的人类模型中细胞治疗的外来体介导的益处

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class="head no_bottom_margin" id="sec1title">IntroductionAbsence of dystrophin in Duchenne muscular dystrophy (DMD) leads to membrane fragility and secondary damage to muscle (both skeletal and cardiac) (). Early disability is due predominantly to the skeletal myopathy, but heart failure is the most common cause of death (). Cardiosphere-derived cells (CDCs) may represent a viable therapeutic option. CDCs are progenitor cells intrinsic to the heart; in clinical trials after myocardial infarction, CDCs promote cardiomyogenesis and reverse established scar (, ). Multiple lines of evidence now indicate that most of the beneficial effects of CDCs are indirect. In the extreme, allogeneic CDCs are cleared completely within several weeks, but their functional and structural benefits persist for at least 6 months (). CDCs secrete diffusible factors that promote angiogenesis, recruit endogenous progenitor cells, and coax surviving heart cells to proliferate (, ); transplanted CDCs suppress maladaptive remodeling (), apoptosis (, ), fibrosis (), and inflammation after myocardial infarction () and in non-ischemic cardiomyopathy (). These diverse mechanisms appear to be mediated via the secretion of exosomes laden with noncoding RNA, including microRNAs (miRNAs) (), consistent with the notion that exosomes contain a plethora of bioactive molecules that target multiple signaling pathways synergistically (). In a murine model of myocardial infarction, CDC-secreted exosomes (CDC exosomes) mimic the functional and structural benefits of CDCs, while blockade of exosome biosynthesis renders CDCs ineffective (href="#bib16" rid="bib16" class=" bibr popnode">Ibrahim et al., 2014). Given the clinical data with CDCs, and the complementarity between their therapeutic actions and the pathophysiological processes underlying Duchenne cardiomyopathy (oxidative stress [href="#bib32" rid="bib32" class=" bibr popnode">Menazza et al., 2010, href="#bib47" rid="bib47" class=" bibr popnode">Williams and Allen, 2007], inflammation [href="#bib45" rid="bib45" class=" bibr popnode">Wehling-Henricks et al., 2010], fibrosis [href="#bib39" rid="bib39" class=" bibr popnode">Tandon et al., 2015], and mitochondrial dysfunction [href="#bib8" rid="bib8" class=" bibr popnode">Burelle et al., 2010]), we reasoned that CDCs and their exosomes might be useful in treating Duchenne cardiomyopathy. Our early work reported in abstract form (href="#bib2" rid="bib2" class=" bibr popnode">Aminzadeh et al., 2014, href="#bib3" rid="bib3" class=" bibr popnode">Aminzadeh et al., 2015a) revealed striking phenotypic correction by CDCs in mdx dystrophic mice, motivating the HOPE-Duchenne clinical trial (href="#bib5" rid="bib5" class=" bibr popnode">Ascheim and Jefferies, 2016) of CDCs in DMD patients. Initially, we had not aspired to restore skeletal muscle function, but merely to offset the pathophysiological consequences of dystrophin deletion in the heart. We now report that CDCs and their secreted exosomes potently improve not only cardiac but also skeletal muscle structure and function, contributing to major systemic benefits after injection of CDCs into the heart. An unanticipated, minor restoration of dystrophin expression was also observed, but this cannot explain all of the observed benefits.
机译：<！-fig ft0-> <！-fig @ position =“ anchor” mode =文章f4-> <！-fig mode =“ anchred” f5-> <！-fig / graphic | fig / alternatives / graphic mode =“ anchored” m1-> class =“ head no_bottom_margin” id =“ sec1title”>简介杜兴氏肌营养不良症（DMD）中缺乏肌营养不良蛋白会导致膜脆性和继发性损伤肌肉（骨骼肌和心脏）（）。早期残疾主要归因于骨骼肌病，但心力衰竭是最常见的死亡原因（）。心球来源的细胞（CDC）可能代表一种可行的治疗选择。 CDC是心脏固有的祖细胞。在心肌梗死后的临床试验中，CDC促进心肌发生并逆转已形成的疤痕（，）。现在有多种证据表明，CDC的大多数有益作用是间接的。在极端情况下，同种异体CDC会在几周内被完全清除，但是它们的功能和结构优势会持续至少6个月（）。 CDC分泌可扩散的因子，这些因子可促进血管生成，募集内源性祖细胞，并诱使幸存的心脏细胞增殖（，）；移植的CDC抑制心肌梗塞后（）和非缺血性心肌病（）中适应不良的重塑（），细胞凋亡（，），纤维化（）和炎症。这些多样的机制似乎是通过分泌含有非编码RNA的外泌体（包括microRNA（miRNA））介导的，这与外泌体包含大量协同作用于多个信号通路的生物活性分子的观点一致。在心肌梗塞的小鼠模型中，CDC分泌的外泌体（CDC外泌体）模仿了CDC的功能和结构优势，而外泌体生物合成的阻断使CDC无效（href =“＃bib16” rid =“ bib16” class =“ bibr popnode“>易卜拉欣等人，2014 ）。给定CDC的临床数据，以及它们的治疗作用与Duchenne心肌病潜在的病理生理过程之间的互补性（氧化应激[href="#bib32" rid="bib32" class=" bibr popnode"> Menazza等， 2010 ，href="#bib47" rid="bib47" class=" bibr popnode">威廉姆斯和艾伦，2007 ]，发炎[href =“＃bib45” rid =“ bib45“ class =” bibr popnode“> Wehling-Henricks等，2010 ]，纤维化[href="#bib39" rid="bib39" class=" bibr popnode"> Tandon等。， 2015 ]和线粒体功能障碍[href="#bib8" rid="bib8" class=" bibr popnode"> Burelle等人，2010 ]），我们认为CDC及其它们的外泌体在治疗杜兴氏心肌病中可能有用。我们的早期工作以抽象形式报告（href="#bib2" rid="bib2" class=" bibr popnode"> Aminzadeh等人，2014 ，href =“＃bib3” rid =“ bib3“ class =” bibr popnode“> Aminzadeh等人，2015a ）揭示了CDC在mdx营养不良小鼠中进行了惊人的表型校正，从而推动了HOPE-Duchenne临床试验（href =”＃bib5“ rid =” bib5“ class =” bibr popnode“> Ascheim and Jefferies，2016 ）。最初，我们并不希望恢复骨骼肌功能，而只是想抵消心脏中肌营养不良蛋白缺失的病理生理后果。我们现在报道，CDC及其分泌的外泌体不仅可以有效改善心脏，而且还可以改善骨骼肌的结构和功能，在将CDC注入心脏后有助于改善系统性。还观察到了肌营养不良蛋白表达的未预期的，较小的恢复，但这不能解释所有观察到的益处。

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