病变远端星形胶质细胞控制小胶质细胞介导的白质修复，这一成果由美国西达赛奈医学中心Joshua E. Burda团队经过不懈努力而取得。该项研究成果发表在2025年12月17日出版的《自然》上。

采用多种转录谱分析方法，小组研究了外伤性脊髓损伤后无主题脊髓的备用区域的LRAs。该研究团队发现LRAs在脊髓损伤后获得了分子上独特的、神经解剖学上受限的反应状态。课题组研究人员在退化的白质中发现了转录上独特的反应性LRAs，它们指导局部小胶质细胞的规范和功能，清除富含脂质的髓磷脂碎片，促进组织修复。促进LRA功能适应的是分泌的基质细胞蛋白CCN1。星形胶质细胞来源的CCN1缺失导致局部小胶质细胞过度、异常激活，其特征是分子规范异常，髓磷脂和轴突碎片在细胞内积聚反映的碎片加工受损，以及脂质代谢失调，脂滴积聚明显衰减。

在机制上，该研究团队发现CCN1结合小胶质细胞SDC4增加脂质储存，将这一信号轴与碎片清除小胶质细胞中重要的修复相关脂质缓冲反应联系起来。因此，星形胶质细胞CCN1耗损导致的小胶质细胞缺陷最终导致白质碎片清除迟钝和脊髓损伤后神经恢复受损。表达CCN1的白质星形胶质细胞是由局部髓鞘损伤诱导的，并在小鼠和人类的多种脱髓鞘疾病中产生，这表明它们在白质修复中具有基本的、进化上保守的作用。他们的研究结果表明，环境特异性线索形成了区域不同的LRA反应状态，并具有功能适应性，协调了神经修复背后的多细胞过程，并影响了疾病结果。

据悉，受损中枢神经系统的剩余区域经历动态重塑，并表现出显著的治疗开发潜力。病变远端星形胶质细胞（LRAs）与活的神经元和胶质细胞相互作用，发生反应性转化，其分子和功能特性尚不清楚。

附：英文原文

Title: Lesion-remote astrocytes govern microglia-mediated white matter repair

Author: McCallum, Sarah, Suresh, Keshav B., Islam, Timothy S., Tripathi, Manish K., Saustad, Ann W., Shelest, Oksana, Patil, Aditya, Lee, David, Kwon, Brandon, Leitholf, Katherine, Yenokian, Inga, Shaka, Sophia E., Beveridge, Connor H., Manchandra, Palak, Randolph, Caitlin E., Meares, Gordon P., Dutta, Ranjan, Plummer, Jasmine, Calsavara, Vinicius F., Kawaguchi, Riki, Knott, Simon R. V., Chopra, Gaurav, Burda, Joshua E.

Issue&Volume: 2025-12-17

Abstract: Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1. Lesion-remote astrocytes (LRAs), which interact with viable neurons and glia, undergo reactive transformations whose molecular and functional properties are poorly understood2. Here, using multiple transcriptional profiling methods, we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury. We show that LRAs acquire a spectrum of molecularly distinct, neuroanatomically restricted reactivity states that evolve after spinal cord injury. We identify transcriptionally unique reactive LRAs in degenerating white matter that direct the specification and function of local microglia that clear lipid-rich myelin debris to promote tissue repair. Fuelling this LRA functional adaptation is the secreted matricellular protein CCN1. Loss of astrocyte-derived CCN1 results in excessive, aberrant activation of local microglia, characterized by abnormal molecular specification, impaired debris processing reflected by the intracellular accumulation of myelin and axon debris, and dysregulated lipid metabolism with distinctive attenuation in lipid droplet accumulation. Mechanistically, we find that CCN1 binds microglial SDC4 to augment lipid storage, linking this signalling axis to a vital repair-associated lipid buffering response in debris-clearing microglia. Accordingly, microglial deficits resulting from astrocyte CCN1 depletion culminate in blunted clearance of white matter debris and impaired neurological recovery from spinal cord injury. Ccn1-expressing white matter astrocytes are induced by local myelin damage and are generated in diverse demyelinating disorders in mice and humans, pointing to their fundamental, evolutionarily conserved role in white matter repair. Our findings show that context-specific cues shape regionally distinct LRA reactivity states with functional adaptations that orchestrate multicellular processes underlying neural repair and influence disease outcome.

DOI: 10.1038/s41586-025-09887-y

Source: https://www.nature.com/articles/s41586-025-09887-y