Cullen Paul F, Sun Daniel
Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States.
Front Ophthalmol (Lausanne). 2023;3. doi: 10.3389/fopht.2023.1217137. Epub 2023 Jul 21.
The role of glia, particularly astrocytes, in mediating the central nervous system's response to injury and neurodegenerative disease is an increasingly well studied topic. These cells perform myriad support functions under physiological conditions but undergo behavioral changes - collectively referred to as 'reactivity' - in response to the disruption of neuronal homeostasis from insults, including glaucoma. However, much remains unknown about how reactivity alters disease progression - both beneficially and detrimentally - and whether these changes can be therapeutically modulated to improve outcomes. Historically, the heterogeneity of astrocyte behavior has been insufficiently addressed under both physiological and pathological conditions, resulting in a fragmented and often contradictory understanding of their contributions to health and disease. Thanks to increased focus in recent years, we now know this heterogeneity encompasses both intrinsic variation in physiological function and insult-specific changes that vary between pathologies. Although previous studies demonstrate astrocytic alterations in glaucoma, both in human disease and animal models, generally these findings do not conclusively link astrocytes to causative roles in neuroprotection or degeneration, rather than a subsequent response. Efforts to bolster our understanding by drawing on knowledge of brain astrocytes has been constrained by the primacy in the literature of findings from peri-synaptic 'gray matter' astrocytes, whereas much early degeneration in glaucoma occurs in axonal regions populated by fibrous 'white matter' astrocytes. However, by focusing on findings from astrocytes of the anterior visual pathway - those of the retina, unmyelinated optic nerve head, and myelinated optic nerve regions - we aim to highlight aspects of their behavior that may contribute to axonal vulnerability and glaucoma progression, including roles in mitochondrial turnover and energy provisioning. Furthermore, we posit that astrocytes of the retina, optic nerve head and myelinated optic nerve, although sharing developmental origins and linked by a network of gap junctions, may be best understood as distinct populations residing in markedly different niches with accompanying functional specializations. A closer investigation of their behavioral repertoires may elucidate not only their role in glaucoma, but also mechanisms to induce protective behaviors that can impede the progressive axonal damage and retinal ganglion cell death that drive vision loss in this devastating condition.
神经胶质细胞，尤其是星形胶质细胞，在介导中枢神经系统对损伤和神经退行性疾病的反应方面，是一个研究日益深入的课题。这些细胞在生理条件下执行多种支持功能，但在受到包括青光眼在内的损伤导致神经元内环境稳态破坏时，会发生行为变化，统称为“反应性”。然而，关于反应性如何有益或有害地改变疾病进展，以及这些变化是否可以通过治疗手段进行调节以改善预后，仍有许多未知之处。从历史上看，在生理和病理条件下，星形胶质细胞行为的异质性都没有得到充分研究，导致对它们在健康和疾病中的作用的理解支离破碎，且常常相互矛盾。由于近年来关注度的提高，我们现在知道这种异质性既包括生理功能的内在差异，也包括不同病理情况下特定损伤引起的变化。尽管先前的研究表明，无论是在人类疾病还是动物模型中，青光眼都会导致星形胶质细胞发生改变，但一般来说，这些发现并没有确凿地将星形胶质细胞与神经保护或神经退行性变的致病作用联系起来，而只是后续反应。通过借鉴脑星形胶质细胞的知识来加强我们理解的努力，受到了文献中突触周围“灰质”星形胶质细胞研究结果主导地位的限制，而青光眼早期的许多退行性变发生在由纤维状“白质”星形胶质细胞构成的轴突区域。然而，通过关注前视觉通路星形胶质细胞的研究结果，即视网膜、无髓鞘视神经头和有髓鞘视神经区域的星形胶质细胞，我们旨在突出它们的行为中可能导致轴突易损性和青光眼进展的方面，包括它们在线粒体更新和能量供应中的作用。此外，我们认为，视网膜、视神经头和有髓鞘视神经的星形胶质细胞，尽管具有共同的发育起源并通过缝隙连接网络相连，但最好将它们理解为存在于明显不同生态位且具有相应功能特化的不同群体。对它们行为模式的更深入研究不仅可能阐明它们在青光眼中的作用，还可能揭示诱导保护性行为的机制，这些保护性行为可以阻止导致这种毁灭性疾病视力丧失的渐进性轴突损伤和视网膜神经节细胞死亡。
