Semel Institute for Neuroscience and Human Behavior and Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1763, USA.
J Neurosci. 2013 Jul 31;33(31):12870-86. doi: 10.1523/JNEUROSCI.2121-13.2013.
Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons.
星形胶质细胞瘢痕环绕中枢神经系统创伤、中风、感染或自身免疫性炎症后的受损组织。它们对于伤口修复至关重要，但也干扰轴突再生。更好地理解星形胶质细胞瘢痕形成的细胞机制、调控和功能，对于开发许多中枢神经系统疾病的安全干预措施至关重要。我们使用野生型和转基因小鼠来量化和剖析这些参数。在挤压性脊髓损伤（SCI）附近，反应性星形胶质细胞在增殖、形态和化学方面表现出异质性表型，这些表型都随损伤距离而变化。SCI 后 14 天成熟瘢痕边界主要由新增殖的星形胶质细胞组成，这些细胞具有长细胞突起，围绕着大、小簇炎性、纤维性和其他细胞。在 SCI 后 5 至 14 天期间形成瘢痕时，源自不同星形胶质细胞的细胞突起会关联成重叠束，这些束可定量重新定向并组织成致密的网状排列。从星形胶质细胞中选择性删除 STAT3 可定量破坏长形星形胶质细胞向瘢痕边界的组织，导致星形胶质细胞无法包围炎性细胞，从而导致这些细胞扩散增加和神经元丢失。在共培养物中，野生型星形胶质细胞会自发将炎性或纤维脑膜细胞聚集到分离的簇中，而 STAT3 缺陷型星形胶质细胞则无法做到这一点。这些发现表明反应性星形胶质细胞存在异质性，并表明瘢痕边界是由新增殖的长形星形胶质细胞形成的，这些细胞通过 STAT3 依赖性机制组织起来，将炎性和纤维性细胞聚集到与包含存活神经元的相邻组织分离的离散区域中。
