The Role of Syndecans in Satellite Cell Function

描述（由申请方提供）：骨骼肌组织在哺乳动物机体的一生中得到修复和维持，但老年人的功能性肌肉丧失和萎缩除外。被认为负责再生和维持骨骼肌组织的成体干细胞是卫星细胞，如此命名是因为其在骨骼肌组织中的解剖学定位夹在肌纤维的质膜和细胞外基质之间。这种独特的生态位对卫星细胞施加了不对称性，允许来自外部环境以及来自底层肌纤维的信号。卫星细胞更新的机制还没有很好地理解，因为许多研究小组已经确定了卫星细胞的亚群，这些亚群表现出增强的移植到骨骼肌组织中。包括我们在内的许多研究小组已经证明，移植的卫星细胞能够在骨骼肌修复过程中自我更新。关于卫星细胞自我更新的一些重要问题尚未得到解决。卫星细胞何时自我更新？卫星电话号码是如何保持的？什么机制负责卫星细胞自我更新？所有卫星细胞都是等价的吗？关于卫星细胞自我更新的这些基本问题仍然没有答案。进一步的分析表明，卫星-SP细胞表达JamB，JamB是一种参与细胞极性的连接粘附蛋白，其结合存在于卫星-SP细胞中的Par复合物。第二，Jam-B细胞表达Par-3，其是不对称的并且与不对称的Syndecan-4共定位。当前瞻性地分离时，多配体聚糖-4 +/Jam-B+培养物维持表达Pax 7的“储备”细胞，而在多配体聚糖-4 +Jam-B-卫星细胞外植体中检测不到Pax 7，所述多配体聚糖-4 +/Jam-B+卫星细胞外植体均终末分化。我们最近提交的手稿提供了一个信号通路的证据，即Par复合物的不对称定位反过来不对称激活p38？？MAPK诱导MyoD在一个子细胞在第一次卫星细胞分裂后外植体。另一个子代未能诱导MyoD并重新获得静止的“储备”表型。我们认为Syndecan-4和Jam- B信号通过细胞外信号协调使卫星细胞进行不对称分裂。我们的实验计划的主要目标是测试这一假设，并提供证据的Syndecan-47 Jam-B复合物，所需的卫星细胞的不对称分裂。

DESCRIPTION (provided by applicant): Skeletal muscle tissue is repaired and maintained for the lifetime of mammalian organisms with the exception of functional muscle loss and atrophy in the aged. The adult stem cell thought to be responsible for re- generating and maintaining skeletal muscle tissue is the satellite cell, so named for its anatomical localization in skeletal muscle tissue sandwiched between the plasma membrane of the myofiber and the extracellular matrix. This unique niche imposes asymmetry on the satellite cell, allowing signaling from the external environment as well as from the underlying myofiber. The mechanisms involved in the renewal of the satellite cell are not well understood as a number of groups have identified subsets of satellite cells that exhibit enhanced engraftment into skeletal muscle tissue. A number of groups, including ours have shown that engrafted satellite cells are capable of self-renewal during skeletal muscle repair. A number of important questions regarding satellite cell self-renewal have not been addressed. When do satellite cells self-renew? How are satellite cell numbers maintained? What mechanisms are responsible for satellite cell self-renewal? Are all satellite cells equivalent? These basic questions regarding satellite cell self-renewal remain unanswered. Additional analysis has revealed that satellite-SP cells express JamB, a junctional adhesion protein involved in cell polarity, which binds the Par complex is present in satellite-SP cells. Second, Jam-B cells express Par-3, which is asymmetric and co-localizes with asymmetric Syndecan-4. When prospectively isolated, Syndecan-4+/Jam-B+ cultures maintain Pax7 expressing "reserve" cells while Pax7 is not detectable in Syndecan-4+Jam-B- satellite cell ex- plants, which all terminally differentiate. Our recently submitted manuscript provides evidence for a signaling pathway whereby asymmetric localization of Par complex in turn asymmetrically activates p38????MAPK inducing MyoD in one daughter cell during the first satellite cell division following explant. The other daughter fails to induce MyoD and re-acquires a quiescent "reserve" phenotype. We propose that Syndecan-4 and Jam- B signaling coordinated by extracellular signals commits a satellite cell to asymmetric division. A primary goal of our experimental plan is to test this hypothesis and provide evidence for a Syndecan-47Jam-B complex that is required for asymmetric division of satellite cells.