Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness. The two most prevalent forms of CMD, collagen VI-related myopathies (COL6RM) and laminin α2 deficient CMD type 1A (MDC1A), are both caused by deficiency or dysfunction of extracellular matrix proteins. Previously, we showed that an intramuscular transplantation of human adipose-derived stem cells (ADSC) into the muscle of the Col6a1−/− mice results in efficient stem cell engraftment, migration, long-term survival, and continuous production of the collagen VI protein, suggesting the feasibility of the systemic cellular therapy for COL6RM. In order for this therapeutic approach to work however, stem cells must be efficiently targeted to the entire body musculature. Thus, the main goal of this study is to test whether muscle homing of systemically transplanted ADSC can be enhanced by employing muscle-specific chemotactic signals originating from CMD-affected muscle tissue. Proteomic screens of chemotactic molecules were conducted in the skeletal muscles of COL6RM- and MDC1A-affected patients and CMD mouse models to define the inflammatory and immune activities, thus, providing potential markers of disease activity or treatment effect. Also using a pre-clinical animal model, recapitulating mild Ullrich congenital muscular dystrophy (UCMD), the therapeutic relevance of identified chemotactic pathways was investigated in vivo, providing a basis for future clinical investigations. Comprehensive proteomic screens evaluating relevant human and mouse skeletal muscle biopsies offered chemotactic axes to enhance directional migration of systemically transplanted cells into CMD-affected muscles, including CCL5-CCR1/3/5, CCL2-CCR2, CXCL1/2-CXCR1,2, and CXCL7-CXCR2. Also, the specific populations of ADSC selected with an affinity for the chemokines being released by damaged muscle showed efficient migration to injured site and presented their therapeutic effect. Collectively, identified molecules provided insight into the mechanisms governing directional migration and intramuscular trafficking of systemically infused stem cells, thus, permitting broad and effective application of the therapeutic adult stem cells for CMD treatment.

中文翻译：

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先天性肌营养不良症相关的炎症趋化因子为有效地将成年治疗性干细胞募集到肌肉中提供了轴

先天性肌营养不良症（CMD）是临床和遗传上异质性的一组神经肌肉疾病，其特征是肌肉无力。CMD的两种最普遍的形式是胶原VI相关肌病（COL6RM）和层粘连蛋白α2缺陷型1A型CMD（MDC1A），都是由细胞外基质蛋白的缺乏或功能障碍引起的。以前，我们表明将人脂肪来源的干细胞（ADSC）肌肉内移植到Col6a1-/-小鼠的肌肉中可导致有效的干细胞移植，迁移，长期存活以及连续产生胶原VI蛋白，提示全身细胞疗法用于COL6RM的可行性。为了使这种治疗方法起作用，必须将干细胞有效地靶向全身肌肉组织。从而，这项研究的主要目的是测试是否可以通过使用源自受CMD影响的肌肉组织的特定于肌肉的趋化信号来增强系统移植的ADSC的肌肉归巢。在受COL6RM和MDC1A影响的患者的骨骼肌和CMD小鼠模型中对趋化分子进行蛋白质组学筛选，以定义炎症和免疫活性，从而提供疾病活性或治疗效果的潜在标志。还使用临床前动物模型，概括了轻度的Ullrich先天性肌营养不良症（UCMD），在体内研究了确定的趋化途径的治疗相关性，为将来的临床研究提供了基础。全面的蛋白质组学筛查评估了相关的人类和小鼠骨骼肌活检，提供了趋化轴，以增强系统移植的细胞向受CMD影响的肌肉中的定向迁移，包括CCL5-CCR1 / 3/5，CCL2-CCR2，CXCL1 / 2-CXCR1,2和CXCL7-CXCR2。而且，选择与受损肌肉释放的趋化因子有亲和力的ADSC的特定人群显示出有效迁移至受伤部位并显示出其治疗效果。集体地，已鉴定的分子提供了对全身注入的干细胞的定向迁移和肌肉内运输的控制机制的见解，从而允许将成年治疗性干细胞广泛有效地用于CMD治疗。CCL2-CCR2，CXCL1 / 2-CXCR1,2和CXCL7-CXCR2。而且，选择与受损肌肉释放的趋化因子有亲和力的ADSC的特定人群显示出有效迁移至受伤部位并显示出其治疗效果。集体地，已鉴定的分子提供了对全身注入的干细胞的定向迁移和肌肉内运输的控制机制的见解，从而允许将成年治疗性干细胞广泛有效地用于CMD治疗。CCL2-CCR2，CXCL1 / 2-CXCR1,2和CXCL7-CXCR2。而且，选择与受损肌肉释放的趋化因子有亲和力的ADSC的特定人群显示出有效迁移至受伤部位并显示出其治疗效果。集体地，已鉴定的分子提供了对全身注入的干细胞的定向迁移和肌肉内运输的控制机制的见解，从而允许将成年治疗性干细胞广泛有效地用于CMD治疗。