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

摘要 杜氏肌营养不良症（DMD）是一种致命的遗传性疾病，其特点是缺乏抗肌萎缩蛋白 表达，导致骨骼肌和心肌的进行性弱化和消耗。目前还 没有治愈DMD的方法。批准的激素治疗有副作用，只能延缓疾病进展 短暂的新兴的基因校正策略，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，因此，新方法 来抑制疾病的发展。肌源性肌肉祖细胞（MPCs），也称为 卫星细胞，随着疾病的进展而变得功能障碍（增殖和分化能力降低）， 与此同时，肌肉再生减少，加重脂肪浸润和纤维化组织积累， 骨骼肌间充质基质细胞（MSC）是成纤维细胞和脂肪细胞的非肌源性祖细胞。 我们和其他人已经报道，在DMD的疾病进展过程中，MSC被激活，并变成 纤维脂肪生成祖细胞（FAP）增殖，诱导MPC功能障碍并导致肌肉病理学。 我们的初步数据表明，FAP表达脂肪祖细胞的标志物，也称为脂肪祖细胞。 基质细胞（ASC），即来源于脂肪组织的MSC，表明ASC是FAP的来源。这个目标 本申请旨在测试DMD发病机制是否可以通过消耗DMD中MSC衍生的FAP来延迟。 小鼠模型在目的1中，将使用自杀性细胞因子进行增殖MSC的诱导性基因消融。 转基因。在目标2中，将使用靶向ASC的猎人杀伤肽进行药理学消融。我们 将测试DMD进展，测量为MPC功能障碍、脂肪浸润、纤维化组织积聚， 所导致的骨骼肌功能丧失可以通过这些实验性治疗来抑制。我们预测 来自营养不良环境的MSC/ASC衍生的FAP的消融将延迟MPC耗竭和DMD， 进展从这些研究中获得的信息将有助于开发新的治疗方法， 肌肉萎缩症

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.