Axonal Regeneration through Regions of Chondroitin Sulfate Proteoglycan Deposition after Spinal Cord Injury: A Balance of Permissiveness and Inhibition
Axonal Regeneration through Regions of Chondroitin Sulfate Proteoglycan Deposition after Spinal Cord Injury: A Balance of Permissiveness and Inhibition
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DOI：
10.1523/jneurosci.23-28-09276.2003
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发表时间：
2003-10
期刊：
影响因子：
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通讯作者：
L. Jones;Dana Sajed;M. Tuszynski
中科院分区：
文献类型：
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作者：
L. Jones;Dana Sajed;M. Tuszynski
某些细胞外基质（ECM）分子在中枢神经系统损伤后的表达增加被认为限制了轴突再生。硫酸软骨素蛋白多糖（CSPGs）是一类体外抑制神经突生长的ECM分子，在中枢神经系统损伤后表达上调。我们研究了几种轴突对这种抑制环境的生长反应，在脊髓病变部位存在细胞成纤维细胞桥，以及在病变部位受到生长因子刺激后（基因修饰的成纤维细胞分泌NGF）。免疫组化分析显示，脊髓损伤（SCI）后，CSPGs NG2、brevican、neurocan、versican和phosphacan在宿主-病变界面密集标记。此外，在对照和分泌ngf的成纤维细胞的移植物中也观察到NG2的强劲表达，以及较小程度的变异。尽管存在这种抑制环境，但仍有几种轴突类型穿透了对照成纤维细胞移植物，包括背柱感觉轴突、红脊轴突和伤害性轴突。分泌ngf的移植物存在时，轴突的生长更明显。共聚焦显微镜显示，在两种类型的移植物中，轴突的生长都优先与富含ng2的基质相关。坐骨神经损伤后，轴突再生成功，NG2表达增加。脊髓损伤和周围神经损伤部位NG2的细胞来源包括雪旺细胞和内皮细胞。值得注意的是，这些相同的细胞来源在病变部位产生细胞粘附分子L1和层粘连蛋白，这些分子都是共定位的。因此，轴突沿着共同表达抑制和允许分子的底物生长，这表明当局部允许信号平衡并超过抑制信号时，再生是成功的。
Increased expression of certain extracellular matrix (ECM) molecules after CNS injury is believed to restrict axonal regeneration. The chondroitin sulfate proteoglycans (CSPGs) are one such class of ECM molecules that inhibit neurite outgrowth in vitro and are upregulated after CNS injury. We examined growth responses of several classes of axons to this inhibitory environment in the presence of a cellular fibroblast bridge in a spinal cord lesion site and after a growth factor stimulus at the lesion site (fibroblasts genetically modified to secrete NGF). Immunohistochemical analysis showed dense labeling of the CSPGs NG2, brevican, neurocan, versican, and phosphacan at the host-lesion interface after spinal cord injury (SCI). Furthermore, robust expression of NG2, and to a lesser extent versican, was also observed throughout grafts of control and NGF-secreting fibroblasts. Despite this inhibitory milieu, several axonal classes penetrated control fibroblast grafts, including dorsal column sensory, rubrospinal, and nociceptive axons. Axon growth was amplified more in the presence of NGF-secreting grafts. Confocal microscopy demonstrated that axon growth was, paradoxically, preferentially associated with NG2-rich substrates in both graft types. NG2 expression also increased after sciatic nerve injury, wherein axons successfully regenerate. Cellular sources of NG2 in SCI and peripheral nerve lesion sites included Schwann cells and endothelial cells. Notably, these same cellular sources in lesion sites produced the cell adhesion molecules L1 and laminin, and these molecules all colocalized. Thus, axons grow along substrates coexpressing both inhibitory and permissive molecules, suggesting that regeneration is successful when local permissive signals balance and exceed inhibitory signals.