Khankan Rana R, Griffis Khris G, Haggerty-Skeans James R, Zhong Hui, Roy Roland R, Edgerton V Reggie, Phelps Patricia E
Department of Integrative Biology and Physiology, and.
Brain Research Institute, University of California-Los Angeles, Los Angeles, California 90095.
J Neurosci. 2016 Jun 8;36(23):6269-86. doi: 10.1523/JNEUROSCI.0085-16.2016.
Multiple neural and peripheral cell types rapidly respond to tissue damage after spinal cord injury to form a structurally and chemically inhibitory scar that limits axon regeneration. Astrocytes form an astroglial scar and produce chondroitin sulfate proteoglycans (CSPGs), activate microglia, and recruit blood-derived immune cells to the lesion for debris removal. One beneficial therapy, olfactory ensheathing cell (OEC) transplantation, results in functional improvements and promotes axon regeneration after spinal cord injury. The lack of an OEC-specific marker, however, has limited the investigation of mechanisms underlying their proregenerative effects. We compared the effects of enhanced green fluorescent protein-labeled fibroblast (FB) and OEC transplants acutely after a complete low-thoracic spinal cord transection in adult rats. We assessed the preservation of neurons and serotonergic axons, the levels of inhibitory CSPGs and myelin debris, and the extent of immune cell activation between 1 and 8 weeks postinjury. Our findings indicate that OECs survive longer than FBs post-transplantation, preserve axons and neurons, and reduce inhibitory molecules in the lesion core. Additionally, we show that OECs limit immune-cell activation and infiltration, whereas FBs alter astroglial scar formation and increase immune-cell infiltration and concomitant secondary tissue damage. Administration of cyclosporine-A to enhance graft survival demonstrated that immune suppression can augment OEC contact-mediated protection of axons and neurons during the first 2 weeks postinjury. Collectively, these data suggest that OECs have neuroprotective and immunomodulatory mechanisms that create a supportive environment for neuronal survival and axon regeneration after spinal cord injury.
Spinal cord injury creates physical and chemical barriers to axon regeneration. We used a complete spinal cord transection model and olfactory ensheathing cell (OEC) or fibroblast (FB; control) transplantation as a repair strategy. OECs, but not FBs, intermingled with astrocytes, facilitated astroglial scar border formation and sequestered invading peripheral cells. OECs attenuated immune cell infiltration, reduced secondary tissue damage, protected neurons and axons in the lesion core, and helped clear myelin debris. Immunosuppression enhanced survival of OECs and FBs, but only OEC transplantation promoted scaffold formation in the lesion site that facilitated axon regeneration and neuron preservation.
脊髓损伤后，多种神经和外周细胞类型会迅速对组织损伤做出反应，形成结构和化学上具有抑制作用的瘢痕，限制轴突再生。星形胶质细胞形成星形胶质瘢痕并产生硫酸软骨素蛋白聚糖（CSPG），激活小胶质细胞，并募集血液来源的免疫细胞至损伤部位清除碎片。一种有效的治疗方法，即嗅鞘细胞（OEC）移植，可改善脊髓损伤后的功能并促进轴突再生。然而，缺乏OEC特异性标志物限制了对其促再生作用机制的研究。我们比较了在成年大鼠完全性胸段低位脊髓横断后立即移植增强型绿色荧光蛋白标记的成纤维细胞（FB）和OEC的效果。我们评估了损伤后1至8周神经元和5-羟色胺能轴突的保存情况、抑制性CSPG和髓磷脂碎片的水平以及免疫细胞激活的程度。我们的研究结果表明，移植后OEC比FB存活时间更长，能保护轴突和神经元，并减少损伤核心部位的抑制性分子。此外，我们发现OEC限制免疫细胞的激活和浸润，而FB则改变星形胶质瘢痕形成并增加免疫细胞浸润以及伴随的继发性组织损伤。给予环孢素A以提高移植物存活率表明，免疫抑制可增强损伤后前2周OEC对轴突和神经元的接触介导保护作用。总体而言，这些数据表明OEC具有神经保护和免疫调节机制，为脊髓损伤后神经元存活和轴突再生创造了一个支持性环境。
脊髓损伤对轴突再生形成了物理和化学屏障。我们使用完全性脊髓横断模型，并将嗅鞘细胞（OEC）或成纤维细胞（FB；对照）移植作为一种修复策略。OEC而非FB与星形胶质细胞混合，促进星形胶质瘢痕边界形成并隔离侵入的外周细胞。OEC减轻免疫细胞浸润，减少继发性组织损伤，保护损伤核心部位的神经元和轴突，并有助于清除髓磷脂碎片。免疫抑制提高了OEC和FB的存活率，但只有OEC移植促进了损伤部位的支架形成，有利于轴突再生和神经元保存。
