High-content screening of human primary muscle satellite cells for new therapies for muscular atrophy/dystrophy.

Lidia S Nierobisz, Bentley Cheatham, Benjamin M Buehrer, Jonathan Z Sexton
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引用次数: 12

Abstract

Myoblast proliferation and differentiation are essential for normal skeletal muscle growth and repair. Muscle recovery is dependent on the quiescent population of muscle stem cells - satellite cells. During muscle injury, satellite cells become mitotically active and begin the repair process by fusing with each other and/or with myofibers. Aging, prolonged inactivity, obesity, cachexia and other muscle wasting diseases are associated with a decreased number of quiescent and proliferating satellite cells, which impedes the repair process. A high-content/high-throughput platform was developed and utilized for robust phenotypic evaluation of human primary satellite cells in vitro for the discovery of chemical probes that may improve muscle recovery. A 1600 compound pilot screen was developed using two highly annotated small molecule libraries. This screen yielded 15 dose responsive compounds that increased proliferation rate in satellite cells derived from a single obese human donor. Two of these compounds remained dose responsive when counter-screened in 3-donor obese superlot. The Alk-5 inhibitor LY364947, was used as a positive control for assessing satellite cell proliferation/delayed differentiation. A multivariate approach was utilized for exploratory data analysis to discover proliferation vs. differentiation-dependent changes in cellular phenotype. Initial screening efforts successfully identified a number of phenotypic outcomes that are associated with desired effect of stimulation of proliferation and delayed differentiation.

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用于肌肉萎缩/营养不良新疗法的人原代肌卫星细胞的高含量筛选。
成肌细胞的增殖和分化对正常骨骼肌的生长和修复至关重要。肌肉恢复依赖于静止的肌肉干细胞-卫星细胞群。在肌肉损伤期间,卫星细胞变得有丝分裂活跃,并通过相互融合和/或与肌纤维融合开始修复过程。衰老、长期不活动、肥胖、恶病质和其他肌肉萎缩疾病与静止和增殖的卫星细胞数量减少有关,这阻碍了修复过程。开发了一个高含量/高通量的平台,用于体外对人原代卫星细胞进行稳健的表型评估,以发现可能改善肌肉恢复的化学探针。使用两个高度注释的小分子文库开发了一个1600化合物先导筛选。该筛选产生了15种剂量反应性化合物,这些化合物增加了来自单个肥胖人类供体的卫星细胞的增殖率。其中两种化合物在3个供体的肥胖超级患者中仍保持剂量反应。Alk-5抑制剂LY364947作为阳性对照,用于评估卫星细胞增殖/延迟分化。采用多变量方法进行探索性数据分析,以发现细胞表型的增殖与分化依赖性变化。最初的筛选工作成功地确定了许多表型结果,这些结果与刺激增殖和延迟分化的预期效果有关。
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