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首页> 外文学位 >The role of satellite cells in skeletal muscle revascularization: A potential factor in muscular dystrophy.
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The role of satellite cells in skeletal muscle revascularization: A potential factor in muscular dystrophy.

机译：卫星细胞在骨骼肌血运重建中的作用：肌营养不良的潜在因素。

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Skeletal muscle regeneration is a multifaceted process requiring the spatial and temporal coordination of myogenesis as well as angiogenesis. While these processes are often studied independently, recent evidence from our lab has shown that the resident adult stem cell population within skeletal muscle, called satellite cells, begins secreting soluble growth factors likely to contribute to the proangiogenic response. It seems plausible that the activation of satellite cells in regenerating muscle plays a critical role in the coordination of these two independent events as both the primary cell for myofiber replacement and as a contributor to revascularization. Several growth factors are secreted by satellite cells, many with proangiogenic properties, including the growth factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). Our lab has recently shown that VEGF is likely to play a role in this satellite cell mediated angiogenic response using an in vitro three dimensional microvascular fragment (MVF) construct both in co-culture with satellite cells as well as from satellite cell conditioned media (CM). We used this MVF culture model coupled with treatment of satellite cell conditioned media in order to investigate the role of HGF in the satellite cell mediated angiogenic response. The overall aim of this study is to investigate the role of HGF as a potential pro-angiogenic factor secreted by satellite cells during skeletal muscle regeneration. Results from the study show elevated HGF protein levels in the satellite cell conditioned media where, upon neutralization of this protein, the angiogenic effect was decreased in a dose dependent manner. This reduction in angiogenesis however was recovered upon addition of recombinant HGF indicating that HGF is indeed a critical protein for the proangiogenic effect of satellite cell CM. One final verification was via infection of satellite cells with an HGFalpha/beta shRNA lentivirus prior to conditioning media, which resulted in a decrease in HGF protein secretion and reduction in angiogenic effect of the CM. With the role for HGF in satellite cell mediated angiogenesis is now becoming apparent; next, we sought to mimic an injury state of muscle by placing satellite cells in hypoxic environments. It is tempting to speculate that satellite cells may increase their angiogenic effect in these hypoxic conditions in order to maximize the revascularization of the injured muscle tissue. Interestingly, it appears that satellite cells 12 decrease their proangiogenic effect if oxygen levels fall below a threshold level. This decrease in pro-angiogenic effect in the hypoxic environment appears to be due to the decrease in HGF expression and protein secretion and is not compensated for by the increase in VEGF secretion also seen in the hypoxic response. Furthermore, the regulation of HGF in these hypoxic conditions appears to be in part due to increased levels of hypoxia inducible factor (HIF), which are acting on the hypoxia response element (HRE) site found on the HGF promoter. In the last set of experiments, this injury response was further investigated as the effect of satellite cell mediated angiogenesis was examined in the disease state of muscular dystrophy. It has previously been shown that there is a reduced number of satellite cells in dystrophic muscle and that the remaining satellite cells appear to have diminished myogenic capacity (Blau, Webster & Pavlath 1983, Schultz, Jaryszak 1985, Webster, Blau 1990, Heslop, Morgan & Partridge 2000) Here, we also observed a reduction in angiogenesis from media conditioned by satellite cells from dystrophic muscle compared to healthy muscle. While HGF gene expression and protein secretion increased in the dystrophic satellite cells, VEGF expression levels were reduced and thus may explain the reduction in angiogenesis. This suggests that the impaired myogenic properties of satellite cells observed in dystrophic muscle may also be accompanied by a diminished angiogenic potential as well. These results also indicate that these impaired satellite cells may contribute to the reduction in capillary density previously observed in dystrophic muscle and may serve as a potential site for therapeutic intervention. Overall, this study further strengthens the case for satellite cells as important mediators of the angiogenic response in regenerating muscle. These results may help explain the ability of the body to regulate the critical process of coordinating myogenesis and angiogenesis during skeletal muscle regeneration. Understanding this process is also important for conditions of muscle degeneration and weakness as seen with aged and dystrophic muscle. It is clear that much work still needs to be done in this area as the implications and potential therapeutic interventions are numerous. It appears that while satellite cells have long been identified and studied primarily as myogenic cells, there may be many more functions they serve as we continue exploring the complex physiological process of skeletal muscle regeneration.
机译：骨骼肌再生是一个多方面的过程，需要在空间和时间上协调肌生成和血管生成。尽管通常独立地研究这些过程，但我们实验室的最新证据表明，骨骼肌中的成年干细胞种群（称为卫星细胞）开始分泌可能有助于促血管生成反应的可溶性生长因子。似乎有可能的是，再生肌中卫星细胞的激活在这两个独立事件的协调中起着关键作用，既是肌纤维置换的主要细胞，又​​是血运重建的因素。卫星细胞分泌几种生长因子，其中许多具有促血管生成特性，包括血管内皮生长因子（VEGF）和肝细胞生长因子（HGF）等生长因子。我们的实验室最近显示，在与卫星细胞以及卫星细胞条件培养基（CM）共培养时，使用体外三维微血管片段（MVF）构建物，VEGF可能在此卫星细胞介导的血管生成反应中起作用）。为了研究HGF在卫星细胞介导的血管生成反应中的作用，我们使用了这种MVF培养模型并结合了卫星细胞条件培养基的处理。这项研究的总体目的是研究HGF作为骨骼肌再生过程中卫星细胞分泌的潜在促血管生成因子的作用。研究结果表明，卫星细胞条件培养基中的HGF蛋白水平升高，该蛋白被中和后，血管生成作用以剂量依赖性方式降低。然而，在加入重组HGF后恢复了血管生成的这种减少，这表明HGF确实是卫星细胞CM促血管生成作用的关键蛋白。最后一项验证是通过在条件培养基之前用HGFalpha /βshRNA慢病毒感染卫星细胞，从而导致HGF蛋白分泌减少和CM的血管生成作用降低。随着HGF在卫星细胞介导的血管生成中的作用，现在变得很明显。接下来，我们试图通过将卫星细胞置于缺氧环境中来模拟肌肉的损伤状态。试图推测卫星细胞可以在这些低氧条件下增加其血管生成作用，以使受伤的肌肉组织的血运重建最大化。有趣的是，如果氧水平低于阈值水平，似乎卫星细胞12会降低其促血管生成作用。在低氧环境中促血管生成作用的这种降低似乎是由于HGF表达和蛋白质分泌的减少所致，并且也不能通过在低氧反应中看到的VEGF分泌的增加来补偿。此外，在这些低氧条件下对HGF的调节似乎部分归因于缺氧诱导因子（HIF）水平的升高，其作用于HGF启动子上的缺氧反应元件（HRE）位点。在最后一组实验中，在肌肉营养不良的疾病状态下检查了卫星细胞介导的血管生成的作用，从而进一步研究了这种损伤反应。以前的研究表明，营养不良的肌肉中卫星细胞的数量减少了，其余的卫星细胞似乎减少了成肌能力（Blau，Webster和Pavlath 1983，Schultz，Jaryszak 1985，Webster，Blau 1990，Heslop，Morgan ＆Partridge 2000）在这里，我们还观察到营养不良的卫星细胞调节的培养基中的血管生成与健康的肌肉相比有所减少。在营养不良的卫星细胞中，HGF基因表达和蛋白质分泌增加，而VEGF表达水平降低，因此可以解释血管生成的减少。这表明在营养不良的肌肉中观察到的卫星细胞的肌原性特性受损也可能伴随着血管生成潜能的降低。这些结果还表明，这些受损的卫星细胞可能有助于降低营养不良性肌肉中先前观察到的毛细血管密度，并可能成为治疗干预的潜在部位。总的来说，这项研究进一步加强了卫星细胞在再生肌肉中作为血管生成反应的重要介质的作用。这些结果可能有助于解释人体调节骨骼肌再生过程中协调肌肉生成和血管生成的关键过程的能力。对于老年和营养不良的肌肉，了解此过程对于肌肉退化和无力的状况也很重要。显然，由于其影响和潜在的治疗干预措施众多，因此在这一领域仍需做大量工作。似乎卫星细胞早已被鉴定和研究为成肌细胞，随着我们继续探索骨骼肌再生的复杂生理过程，它们可能还会发挥更多的功能。

著录项

  • 作者

    Flann, Kyle L.;

  • 作者单位

    The University of Arizona.;

  • 授予单位 The University of Arizona.;
  • 学科 Physiology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 185 p.
  • 总页数 185
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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