Department of Physiology and Cell Biology, Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio 43210, USA.
J Neurosci. 2011 Oct 19;31(42):15173-87. doi: 10.1523/JNEUROSCI.3441-11.2011.
Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges on which axons traverse. We have shown that intrathecal administration of transforming growth factor α (TGFα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGFα directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth. Overexpression of TGFα in vivo by intraparenchymal adeno-associated virus injection adjacent to the injury site enhances cell proliferation, alters astrocyte distribution, and facilitates increased axonal penetration at the rostral lesion border. To determine whether endogenous EGFR activation is required after injury, SCI was also performed on Velvet (C57BL/6J-Egfr(Vel)/J) mice, a mutant strain with defective EGFR activity. The affected mice exhibited malformed glial borders, larger lesions, and impaired recovery of function, indicating that intrinsic EGFR activation is necessary for neuroprotection and normal glial scar formation after SCI. By further stimulating precursor proliferation and modifying glial activation to promote a growth-permissive environment, controlled stimulation of EGFR at the lesion border may be considered in the context of future strategies to enhance endogenous cellular repair after injury.
星形胶质细胞对脊髓损伤 (SCI) 后的修复和恢复既有好处也有坏处。这些活跃的细胞是形成生长抑制性胶质瘢痕的主要原因，但它们也具有神经保护作用，并能形成支持轴突穿越的生长支持性桥。我们已经表明，鞘内给予转化生长因子 α (TGFα) 到挫伤的小鼠脊髓中，可以增强损伤部位内的星形胶质细胞浸润和轴突生长，但这些影响的机制尚不清楚。本研究表明，表皮生长因子受体 (EGFR) 在 SCI 后早期主要由星形胶质细胞和神经前体细胞上调。TGFα 在体外直接激活这些细胞上的 EGFR，诱导其增殖、迁移，并转化为支持强大神经突生长的表型。通过在损伤部位附近的脑实质内腺相关病毒注射在体内过表达 TGFα，可增强细胞增殖，改变星形胶质细胞分布，并促进在损伤部位的前端边界增加轴突穿透。为了确定损伤后是否需要内源性 EGFR 激活，我们还在 Velvet (C57BL/6J-Egfr(Vel)/J) 小鼠（一种 EGFR 活性缺陷的突变株）中进行了 SCI。受影响的小鼠表现出畸形的胶质边界、更大的损伤和功能恢复受损，表明内在 EGFR 激活是 SCI 后神经保护和正常胶质瘢痕形成所必需的。通过进一步刺激前体细胞增殖和改变胶质激活以促进生长许可环境，在未来的策略中，可以考虑在损伤边界处对 EGFR 进行受控刺激，以增强内源性细胞修复。
