Aging dependent transformation of oligodendrocyte precursor cells

总结： 为了维持神经信号并在整个生命过程中实现可塑性，神经系统依赖于稳态 与产生和修饰细胞外基质的不同胶质细胞群体的相互作用， 离子和神经递质，提供代谢支持，并促进电路的功能重组， 对活动模式变化的反应。虽然大多数神经胶质细胞的研究都集中在三个主要的 神经胶质细胞的种类-星形胶质细胞、少突胶质细胞和小神经胶质细胞-哺乳动物脑还含有丰富的， 称为少突胶质细胞前体细胞（OPC或NG 2胶质细胞）的胶质祖细胞的高度动态群体。 这些谱系限制的祖细胞在产生少突胶质细胞中起着关键作用，以使得能够产生 在运动学习过程中新的髓鞘和通过疾病破坏的髓鞘的替代，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区域， 白色物质，但随着年龄的增长，其行为表现出深刻的变化， 增殖和分化。新出现的证据表明，OPCs不仅仅是作为祖细胞， 少突胶质细胞，因为它们发现在没有髓鞘的区域，并且像小胶质细胞一样，OPCs迁移到 损伤部位并导致瘢痕形成，与其在少突分化中的作用无关的特征， 髓鞘修复OPCs与小胶质细胞有许多共同的其他特征-它们以相似的密度存在，保持 网格状分布，具有分支，径向导向的过程，并且是高度动态的，连续的 用能动的丝状伪足探索周围环境此外，最近的证据表明， 可转化为炎性OPCs（iOPCs），通过MHC吞噬并呈递外源性抗原 当暴露于炎性细胞因子时，它们可能是I类和II类，这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响应于炎症而经历表型变化， 深刻地影响着衰老的大脑，但对OPCs在这种背景下的作用知之甚少，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OPC的询问。OPC在可用单细胞中的代表性不足 RNA-seq数据集，目前还没有专门设计的研究来定义它们的变化是如何发生的。 老化性能受其先前行为的影响。我们将利用各种方法 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， 这些普遍存在的神经胶质细胞的年龄依赖性变化的后果。新的洞察力提供了这些 研究可能会导致对这些神经胶质细胞所起的稳态作用的更深入的理解，并揭示 新的方法来恢复他们的再生潜力，以维持整个生命的大脑功能。

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.