High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury
High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury
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DOI：
10.1088/1741-2560/8/4/046033
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发表时间：
2011-08-01
影响因子：
4
通讯作者：
Schmidt, Christine E.
中科院分区：
文献类型：
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作者：
Khaing, Zin Z.;Milman, Brian D.;Schmidt, Christine E.
脊髓损伤（SCI）后再生的一个主要障碍是轴突穿透瘢痕组织并生长的能力。脊髓损伤后，炎性细胞、星形胶质细胞和脑膜细胞都在胶质瘢痕的形成中发挥作用。此外，天然高分子量（MW）透明质酸（HA）（细胞外基质的一种组分）的降解已显示可诱导星形胶质细胞的活化和增殖。然而，目前尚不清楚天然HA的降解是否真的增强了神经胶质瘢痕形成。我们假设SCI后高分子量HA（降解有限的HA）的存在将减少胶质瘢痕形成。在这里，我们证明，高分子量HA降低细胞增殖，并减少硫酸软骨素蛋白聚糖（CSPG）的生产在培养的新生儿和成人星形胶质细胞。此外，刚度匹配的高分子量HA水凝胶交联，以抵抗降解植入脊髓背侧半切损伤的大鼠模型。在急性时间点（损伤后1、3和10天），在植入HA水凝胶植入物的动物中病变部位检测到的免疫细胞（巨噬细胞和小胶质细胞）数量显著减少。植入HA植入物的受损动物在损伤后十天也表现出显着较低的CSPG表达。在损伤后9周，具有HA水凝胶植入物的动物表现出显著降低的星形胶质细胞反应，但没有显著改变CSPG表达。结合，这些数据表明，高分子量HA，当稳定降解，减轻星形胶质细胞在体外和体内的激活。HA植入物的存在也与SCI后10天CSPG沉积的显著减少相关。因此，基于HA的水凝胶系统具有将不期望的瘢痕形成最小化作为SCI后未来修复策略的一部分的巨大潜力。
A major hurdle for regeneration after spinal cord injury (SCI) is the ability of axons to penetrate and grow through the scar tissue. After SCI, inflammatory cells, astrocytes and meningeal cells all play a role in developing the glial scar. In addition, degradation of native high molecular weight (MW) hyaluronic acid (HA), a component of the extracellular matrix, has been shown to induce activation and proliferation of astrocytes. However, it is not known if the degradation of native HA actually enhances glial scar formation. We hypothesize that the presence of high MW HA (HA with limited degradation) after SCI will decrease glial scarring. Here, we demonstrate that high MW HA decreases cell proliferation and reduces chondroitin sulfate proteoglycan (CSPG) production in cultured neonatal and adult astrocytes. In addition, stiffness-matched high MW HA hydrogels crosslinked to resist degradation were implanted in a rat model of spinal dorsal hemisection injury. The numbers of immune cells (macrophages and microglia) detected at the lesion site in animals with HA hydrogel implants were significantly reduced at acute time points (one, three and ten days post-injury). Lesioned animals with HA implants also exhibited significantly lower CSPG expression at ten days post-injury. At nine weeks post-injury, animals with HA hydrogel implants exhibited a significantly decreased astrocytic response, but did not have significantly altered CSPG expression. Combined, these data suggest that high MW HA, when stabilized against degradation, mitigates astrocyte activation in vitro and in vivo. The presence of HA implants was also associated with a significant decrease in CSPG deposition at ten days after SCI. Therefore, HA-based hydrogel systems hold great potential for minimizing undesired scarring as part of future repair strategies after SCI.