Satellite cells are the canonical muscle stem cells that regenerate damaged skeletal muscle. Loss of function of these cells has been linked to reduced muscle repair capacity and compromised muscle health in acute muscle injury and congenital neuromuscular diseases. To identify new pathways that can prevent loss of skeletal muscle function or enhance regenerative potential, we established an imaging-based screen capable of identifying small molecules that promote the expansion of freshly isolated satellite cells. We found several classes of receptor tyrosine kinase (RTK) inhibitors that increased freshly isolated satellite cell numbers in vitro. Further exploration of one of these compounds, the RTK inhibitor CEP-701 (also known as lestaurtinib), revealed potent activity on mouse satellite cells both in vitro and in vivo. This expansion potential was not seen upon exposure of proliferating committed myoblasts or non-myogenic fibroblasts to CEP-701. When delivered subcutaneously to acutely injured animals, CEP-701 increased both the total number of satellite cells and the rate of muscle repair, as revealed by an increased cross-sectional area of regenerating fibers. Moreover, freshly isolated satellite cells expanded ex vivo in the presence of CEP-701 displayed enhanced muscle engraftment potential upon in vivo transplantation. We provide compelling evidence that certain RTKs, and in particular RET, regulate satellite cell expansion during muscle regeneration. This study demonstrates the power of small molecule screens of even rare adult stem cell populations for identifying stem cell-targeting compounds with therapeutic potential.

中文翻译：

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原代肌肉干细胞化学筛选揭示的促肌原性小分子

卫星细胞是典型的肌肉干细胞，可再生受损的骨骼肌。这些细胞的功能丧失与急性肌肉损伤和先天性神经肌肉疾病中肌肉修复能力下降和肌肉健康受损有关。为了确定可以防止骨骼肌功能丧失或增强再生潜力的新途径，我们建立了一个基于成像的屏幕，能够识别促进新鲜分离的卫星细胞扩增的小分子。我们发现了几类受体酪氨酸激酶 (RTK) 抑制剂，它们在体外增加了新鲜分离的卫星细胞数量。对其中一种化合物 RTK 抑制剂 CEP-701（也称为来他替尼）的进一步探索揭示了在体外和体内对小鼠卫星细胞的有效活性。在增殖的定型成肌细胞或非成肌成纤维细胞暴露于 CEP-701 时，没有看到这种扩张潜力。当皮下注射给急性受伤的动物时，CEP-701 增加了卫星细胞的总数和肌肉修复的速度，正如再生纤维横截面积增加所揭示的那样。此外，在 CEP-701 存在下离体扩增的新鲜分离的卫星细胞在体内移植后显示出增强的肌肉植入潜力。我们提供了令人信服的证据，表明某些 RTK，特别是 RET，在肌肉再生过程中调节卫星细胞的扩张。这项研究证明了即使是罕见的成体干细胞群的小分子筛选在鉴定具有治疗潜力的干细胞靶向化合物方面的能力。