The Role of Syndecans in Satellite Cell Function

描述（由申请人提供）：骨骼肌组织在哺乳动物生物体的一生中被修复和维持，但老年人的功能性肌肉损失和萎缩除外。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夹在肌纤维质膜和细胞外基质之间的解剖位置而得名。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底层肌纤维的信号。卫星细胞更新的机制尚不清楚，因为许多研究小组已经确定了卫星细胞亚群，它们表现出增强的植入骨骼肌组织。包括我们在内的一些研究小组已经表明，在骨骼肌修复过程中，植入的卫星细胞能够自我更新。关于卫星小区自我更新的一些重要问题尚未得到解决。卫星细胞什么时候自我更新？卫星小区号码如何维持？卫星细胞自我更新的机制是什么？所有的卫星基站都是一样的吗？这些关于卫星细胞自我更新的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，这是一种与细胞极性相关的连接粘附蛋白，它与卫星sp细胞中的Par复合物结合。其次，Jam-B细胞表达不对称的Par-3，与不对称的Syndecan-4共定位。当预期分离时，Syndecan-4+/Jam-B+培养维持表达Pax7的“储备”细胞，而在Syndecan-4+Jam-B-卫星细胞前植物中检测不到Pax7，这些细胞都是终末分化的。我们最近提交的论文为Par复合物的不对称定位反过来不对称激活p38????的信号通路提供了证据在外植体后第一个卫星细胞分裂过程中，MAPK在一个子细胞中诱导MyoD。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信号在细胞外信号的协调下使卫星细胞发生不对称分裂。我们实验计划的一个主要目标是验证这一假设，并为Syndecan-47Jam-B复合体提供证据，该复合体是卫星细胞不对称分裂所必需的。

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. PUBLIC HEALTH RELEVANCE: Skeletal muscle is essential for respiration, locomotion, and elimination of waste. Severe loss of skeletal muscle is catastrophic, shortening lifespan, dramatically reducing overall quality of life and incurring significant health care costs. Severe loss of muscle function occurs during normal aging and in neuromuscular diseases. The loss of skeletal muscle function is likely due to loss of regenerative capacity and the ability of adult muscle stem cells to renew themselves. We propose research to better understand how adult muscle stem cells are regulated aiding in the development of stem cell therapies.