Centre for Craniofacial and Regenerative Biology, King's College London, Guy's Hospital, London, London SE1 9RT, UK.
Oral Clinical Research Unit, King's College London, London, London SE1 9RT, UK.
Open Biol. 2023 Sep;13(9):230037. doi: 10.1098/rsob.230037. Epub 2023 Sep 20.
Skeletal muscle is highly regenerative and is mediated by a population of migratory adult muscle stem cells (muSCs). Effective muscle regeneration requires a spatio-temporally regulated response of the muSC population to generate sufficient muscle progenitor cells that then differentiate at the appropriate time. The relationship between muSC migration and cell fate is poorly understood and it is not clear how forces experienced by migrating cells affect cell behaviour. We have used zebrafish to understand the relationship between muSC cell adhesion, behaviour and fate . Imaging of pax7-expressing muSCs as they respond to focal injuries in trunk muscle reveals that they migrate by protrusive-based means. By carefully characterizing their behaviour in response to injury we find that they employ an adhesion-dependent mode of migration that is regulated by the RhoA kinase ROCK. Impaired ROCK activity results in reduced expression of cell cycle genes and increased differentiation in regenerating muscle. This correlates with changes to focal adhesion dynamics and migration, revealing that ROCK inhibition alters the interaction of muSCs to their local environment. We propose that muSC migration and differentiation are coupled processes that respond to changes in force from the environment mediated by RhoA signalling.
骨骼肌具有很强的再生能力，由一群迁移的成年肌肉干细胞（muSCs）介导。有效的肌肉再生需要 muSC 群体的时空调节反应，以产生足够的肌肉祖细胞，然后在适当的时间分化。muSC 迁移和细胞命运之间的关系尚不清楚，也不清楚迁移细胞经历的力如何影响细胞行为。我们使用斑马鱼来了解 muSC 细胞黏附、行为和命运之间的关系。当 pax7 表达的 muSCs 对躯干肌肉的局灶性损伤做出反应时，对其进行成像，结果表明它们通过基于突起的方式迁移。通过仔细描述它们对损伤的反应行为，我们发现它们采用依赖黏附的迁移模式，该模式受 RhoA 激酶 ROCK 调节。ROCK 活性受损会导致细胞周期基因表达减少，再生肌肉中分化增加。这与焦点黏附动力学和迁移的变化相关，表明 ROCK 抑制改变了 muSCs 与其局部环境的相互作用。我们提出 muSC 迁移和分化是耦联过程，它们响应由 RhoA 信号介导的来自环境的力的变化。
