The Role of Syndecans in Satellite Cell Function

说明(申请人提供)：骨骼肌组织在哺乳动物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，因其在骨骼肌组织中的解剖定位而得名，这些组织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，允许来自外部环境和潜在的肌纤维的信号。有关卫星细胞更新的机制还不是很清楚，因为一些研究小组已经确定了卫星细胞的亚群，显示出增强的植入到骨骼肌组织中。包括我们在内的许多研究小组已经证明，植入的卫星细胞能够在骨骼肌修复过程中自我更新。关于卫星单元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？卫星细胞的数量是如何维持的？卫星细胞自我更新的机制是什么？所有的卫星单元都是等同的吗？这些关于卫星细胞自我更新的基本问题仍然没有得到回答。进一步的分析表明，卫星SP细胞表达JAMB，一种与细胞极性有关的连接黏附蛋白，它结合PAR复合体存在于卫星SP细胞中。第二，JAM-B细胞表达不对称的PAR-3，它与不对称的Syndecan-4共定位。当预期分离时，Syndecan-4+/Jam-B+培养物保持Pax7的表达，而在Syndecan-4+Jam-B-卫星细胞外植体中检测不到Pax7，这些细胞都是终末分化的。我们最近提交的论文为PAR复合体的不对称定位进而不对称地激活p38？MAPK在外植体后的第一次卫星细胞分裂中诱导一个子细胞中的MyoD的信号通路提供了证据。另一个女儿未能诱导MyoD，并重新获得了一种静止的“储备”表型。我们认为，在胞外信号的协调下，Syndecan-4和Jam-B信号使卫星细胞进行不对称分裂。我们实验计划的一个主要目标是检验这一假说，并为卫星细胞不对称分裂所需的Syndecan-47Jam-B复合体提供证据。

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.