Aging dependent transformation of oligodendrocyte precursor cells

摘要： 神经系统依靠体内平衡来维持神经信号并使其在整个生命中具有可塑性。 与不同群体的神经胶质细胞相互作用，产生和修改细胞外基质，移除 离子和神经递质，提供代谢支持，促进脑内神经回路的功能重组 对不断变化的活动模式作出反应。尽管大多数对神经胶质细胞的研究主要集中在三个主要方面 胶质细胞的种类--星形胶质细胞、少突胶质细胞和小胶质细胞--哺乳动物的大脑也含有丰富的、 被称为少突胶质前体细胞(OPC或NG2胶质细胞)的高度动态的神经胶质前体细胞群体。 这些血统受限的祖细胞在产生少突胶质细胞以使其能够产生 运动学习期间的新髓鞘和因疾病而被破坏的髓鞘的替换，例如 多发性硬化症(MS)和肌萎缩侧索硬化症(ALS)。OPC仍然广泛分布在灰色和 白质贯穿一生，但随着年龄的增长表现出深刻的行为变化，包括减少 增殖分化。新出现的证据表明，OPC不仅仅是OPC的祖先 少突胶质细胞，因为它们存在于没有髓鞘的区域，并且像小胶质细胞一样，OPC迁移到 损伤部位和促进瘢痕形成的特征，与它们在少突胶质细胞形成和形成中的作用无关 髓鞘修复。OPC与小胶质细胞有许多其他特征--它们以相似的密度存在， 网格状的分布，具有分支的、面向辐射的过程，并且是高度动态的、连续的 用活动的丝状足纲探索它们周围的环境。此外，最近的证据表明，OPC 可以转化为炎症性OPC(IOPC)，通过MHC吞噬并递送外源抗原 当暴露在炎性细胞因子下时，I类和II类，表明它们可能调节组织炎症。 虽然已知小胶质细胞和星形胶质细胞在炎症反应中经历表型变化， 深刻地影响老化的大脑，人们对OPC在这方面的作用知之甚少，尽管它们 大脑回路中的持久性。在某种程度上，这种知识的缺乏源于有限的分子和生理 已经在体内完成的对OPC的审问。OPC在可用单元格中的比例偏低 Rna-seq数据集，目前还没有专门设计的研究来定义它们的 随着年龄的增长，房产会受到其先前行为的影响。我们将利用各种不同的方法 以及我们在生理学、分子和计算生物学方面的综合专业知识，以确定原因和 这些无处不在的神经胶质细胞的年龄相关性变化的后果。这些提供的新洞察力 研究可能会导致对这些神经胶质细胞执行的体内平衡作用的更深入的理解，并揭示 恢复其再生潜力以维持其终生大脑功能的新方法。

Summary: To sustain neural signaling and enable plasticity throughout life, the nervous system relies on homeostatic interactions with a diverse population of glial cells, which create and modify the extracellular matrix, remove ions and neurotransmitters, provide metabolic support and promote functional reorganization of circuits in response to changing patterns of activity. Although most studies of glial cells have focused on the three main classes of glia – astrocytes, oligodendrocytes and microglia – the mammalian brain also contains an abundant, highly dynamic population of glial progenitors termed oligodendrocyte precursor cells (OPCs or NG2 glia). These lineage restricted progenitors play crucial roles in generating oligodendrocytes to enable production of new myelin sheaths during motor learning and replacement of myelin destroyed through disease, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). OPCs remain widely distributed in gray and white matter throughout life, but exhibit profound changes in behavior with aging, including reduced proliferation and differentiation. Emerging evidence suggests that OPCs do more than serve as progenitors for oligodendrocytes, as they are found in regions where there is no myelin, and like microglia, OPCs migrate to sites of injury and contribute to scar formation, features unrelated to their role in oligodendrogenesis and myelin repair. OPCs share many other features with microglia – they are present at a similar density, maintain a grid-like distribution, possess ramified, radially-oriented processes and are highly dynamic, continuously exploring their surrounding environment with motile filopodia. Moreover, recent evidence indicates that OPCs can transform into inflammatory OPCs (iOPCs) that engulf and present exogenous antigens through MHC class I and II when exposed to inflammatory cytokines, suggesting that they may modulate tissue inflammation. While microglia and astrocytes are known to undergo phenotypic changes in response to inflammation that profoundly influence the aging brain, much less is known about the role of OPCs in this context, despite their persistence in brain circuits. In part, this lack of knowledge stems from the limited molecular and physiological interrogation of OPCs that has been completed in vivo. OPCs are underrepresented in available single cell RNA-seq datasets and there have been no studies specifically designed to define how changes in their properties with aging are influenced by their prior behavior. We will leverage a diverse array of methodologies and our combined expertise in physiology, molecular and computational biology to define the causes and consequences of age-dependent changes in these ubiquitous glial cells. The new insight provided by these studies may lead to a deeper understanding of the homeostatic roles performed by these glial cells, and reveal new approaches for rejuvenating their regenerative potential to sustain brain function throughout life.