Section of Pharmacology, Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", via Orabona 4-Campus, 70125 Bari, Italy.
Cells. 2020 Jul 9;9(7):1659. doi: 10.3390/cells9071659.
The muscle stem cells niche is essential in neuromuscular disorders. Muscle injury and myofiber death are the main triggers of muscle regeneration via satellite cell activation. However, in degenerative diseases such as muscular dystrophy, regeneration still keep elusive. In these pathologies, stem cell loss occurs over time, and missing signals limiting damaged tissue from activating the regenerative process can be envisaged. It is unclear what comes first: the lack of regeneration due to satellite cell defects, their pool exhaustion for degeneration/regeneration cycles, or the inhibitory mechanisms caused by muscle damage and fibrosis mediators. Herein, Duchenne muscular dystrophy has been taken as a paradigm, as several drugs have been tested at the preclinical and clinical levels, targeting secondary events in the complex pathogenesis derived from lack of dystrophin. We focused on the crucial roles that pro-inflammatory and pro-fibrotic cytokines play in triggering muscle necrosis after damage and stimulating satellite cell activation and self-renewal, along with growth and mechanical factors. These processes contribute to regeneration and niche maintenance. We review the main effects of drugs on regeneration biomarkers to assess whether targeting pathogenic events can help to protect niche homeostasis and enhance regeneration efficiency other than protecting newly formed fibers from further damage.
肌肉干细胞生态位对于神经肌肉疾病至关重要。肌肉损伤和肌纤维死亡是通过卫星细胞激活来启动肌肉再生的主要触发因素。然而，在诸如肌肉萎缩症等退行性疾病中，再生仍然难以实现。在这些病理情况下，干细胞会随着时间的推移而丢失，并且可以想象到限制受损组织激活再生过程的缺失信号。目前尚不清楚是什么导致了缺乏再生：是由于卫星细胞缺陷导致的再生不足，还是由于肌肉损伤和纤维化介质引起的抑制机制导致的它们的池耗尽。在此，以杜氏肌营养不良症为例，已经在临床前和临床水平上测试了几种药物，这些药物针对的是缺乏肌营养不良蛋白的复杂发病机制中的继发事件。我们重点研究了促炎和促纤维化细胞因子在损伤后引发肌肉坏死以及刺激卫星细胞激活和自我更新、生长和机械因素方面的关键作用。这些过程有助于再生和生态位维持。我们回顾了药物对再生生物标志物的主要影响，以评估靶向致病事件是否有助于保护生态位平衡并提高再生效率，而不仅仅是保护新形成的纤维免受进一步损伤。
