Ablation of Non-Myogenic Progenitor Cells as a New Therapeutic Approach to Duchenne Muscular Dystrophy

摘要 Duchenne肌营养不良症(DMD)是一种以肌营养不良蛋白缺乏为特征的致命遗传病 表达，导致骨骼肌和心肌逐渐衰弱和消瘦。目前，有 没有治愈DMD的方法。批准的激素治疗有副作用，只会延缓疾病的进展。 暂时的。新出现的基因纠正策略虽然在小鼠模型中有效，但可能是有限的。 由于与病毒介导的基因治疗相关的问题，对患者的直接价值。因此，新的方法 为了抑制疾病的发展是必要的。肌源性肌祖细胞(MPC)也称为 随着疾病的发展，卫星细胞会变得功能失调(增殖和分化能力降低)， 巧合的是，肌肉再生减少，脂肪渗透加剧，纤维组织积聚 骨骼肌。间充质基质细胞(MSCs)是成纤维细胞和脂肪细胞的非肌源性前体细胞。 我们和其他人已经报道，在DMD的疾病进展过程中，MSCs被激活，并转化为 成纤维脂肪前体细胞(FAP)可以增殖，导致MPC功能障碍，并有助于肌肉病理。 我们的初步数据表明，FAP表达脂肪祖细胞的标志，也称为脂肪 间质细胞(ASCs)，即来源于脂肪组织的MSCs，提示ASCs是FAPs的来源。这样做的目的是 应用于测试是否可以通过耗尽MSC来源的FAP来延缓DMD的发病 老鼠模型。在目标1中，将使用自杀的方法对增殖中的MSC进行可诱导的遗传消融 转基因。在目标2中，将使用针对ASCs的猎杀多肽进行药理消融。我们 将测试DMD进展，测量MPC功能障碍，脂肪渗透，纤维组织堆积，以及 由此造成的骨骼肌功能的丧失，可以通过这些实验性的治疗方法来抑制。我们预测 来自营养不良环境的MSCs/ASCs来源的FAP的消融将延缓MPC耗竭和DMD 进步。从这些研究中获得的信息将有助于开发新的治疗方法 肌肉营养不良症。

Abstract Duchenne muscular dystrophy (DMD) is a deadly genetic disease characterized by a lack of dystrophin expression, resulting in progressive weakening and wasting of skeletal and cardiac muscles. Currently, there is no cure for DMD. The approved hormonal treatments have side effects and delay the disease progression only transiently. The emerging gene correction strategies, although effective in mouse models, are likely to be of limited immediate value to patients due to issues associated with virus-mediated gene therapy. Therefore, new approaches to suppress the disease progression are needed. Myogenic muscle progenitor cells (MPCs), also known as satellite cells, become dysfunctional (reduced proliferation and differentiation capacities) as disease progresses, coincidentally with reduced muscle regeneration, aggravating fatty infiltration, and fibrotic tissue accumulation in skeletal muscle. Mesenchymal stromal cells (MSCs) are non-myogenic progenitors of fibroblasts and adipocytes. We and others have reported that MSCs get activated during the disease progression in DMD and turn into fibroadipogenic progenitors (FAPs) that proliferate, induce MPC dysfunction and contribute to muscle pathology. Our preliminary data indicates that FAPs express markers of adipocyte progenitors, also known as adipose stromal cells (ASCs), the MSCs derived from fat tissue, suggesting ASCs as a source of FAPs. The goal of this application is to test whether DMD pathogenesis can be delayed via depletion of MSC-derived FAPs in the mouse model. In Aim 1, an inducible genetic ablation of proliferating MSC will be performed using a suicide transgene. In Aim 2, pharmacological ablation will be performed with a hunter-killer peptide targeting ASCs. We will test if DMD progression, measured as MPC dysfunction, fatty infiltration, fibrotic tissue accumulation, and the resulting loss of skeletal muscle function, can be suppressed by these experimental treatments. We predict that ablation of FAPs derived from MSCs/ASCs from the dystrophic milieu will delay MPC depletion and DMD progression. Information obtained from these studies will help develop new therapeutic approaches for treating muscular dystrophy.