Department of Physiology, Institute of Stem Cells and Regenerative Medicine, Guangdong Medical University, Dongguan, China.
Hand and Foot Surgery and Reparative and Reconstruction Surgery Center, The Second Hospital of Jilin University, Changchun, China.
Tissue Eng Part A. 2019 Oct;25(19-20):1381-1395. doi: 10.1089/ten.TEA.2018.0282. Epub 2019 May 2.
Spinal root avulsion typically leads to massive motoneuron death and severe functional deficits of the target muscles. Multiple pathological factors such as severe neuron loss, induction of inhibitory molecules, and insufficient regeneration are responsible for the poor functional recovery. Leucine-rich repeat and immunoglobulin-like domain-containing Nogo receptor-interacting protein 1 (LINGO-1), a central nervous system (CNS)-specific transmembrane protein that is selectively expressed on neurons and oligodendrocytes, serves as a potent negative mediator of axonal regeneration and myelination in CNS injuries and diseases. Although accumulating evidence has demonstrated improvement in axonal regeneration and neurological functions by LINGO-1 antagonism in CNS damage, the possible effects of LINGO-1 in spinal root avulsion remain undiscovered. In this study, a LINGO-1 knockdown strategy using lentiviral vectors encoding LINGO-1 short hairpin interfering RNA (shRNA) delivered by the Pluronic F-127 (PF-127) hydrogel was described after brachial plexus avulsion (BPA). We provide evidence that following BPA and immediate reimplantation, transplantation of LINGO-1 shRNA lentiviral vectors encapsulated by PF-127 rescued the injured motoneurons, enhanced axonal outgrowth and myelination, rebuilt motor endplates, facilitated the reinnervation of terminal muscles, improved angiogenesis, and promoted recovery of avulsed forelimbs. Altogether, these data suggest that delivery of LINGO-1 shRNA by a gel scaffold is a potential therapeutic approach for root avulsion. Impact Statement In this study, we attempted transplantation of lentivirus (LV)/leucine-rich repeat and immunoglobulin-like domain-containing Nogo receptor-interacting protein 1 (LINGO-1)-short hairpin interfering RNA (shRNA) encapsulated by the Pluronic F-127 (PF-127) hydrogel into a brachial plexus avulsion (BPA)-reimplantation model. We found that administration of LV/LINGO-1 shRNA facilitates neuron survival and axonal regeneration, attenuates muscle atrophy and motor endplate (MEP) loss, enhances neovascularization, and promotes functional recovery in BPA rats. Co-transplantation of LV/LINGO-1 shRNA and gel reinforces the survival-promoting effect, axonal outgrowth, and angiogenesis in comparison with LV/LINGO-1 shRNA application alone. Our research provides evidence that LV /LINGO-1 shRNA delivered by PF-127 represents a new treatment strategy for BPA repair.
神经根撕脱通常导致大量运动神经元死亡和靶肌肉严重功能障碍。多种病理因素，如严重神经元丢失、抑制分子诱导和再生不足，导致功能恢复不良。富含亮氨酸重复和免疫球蛋白样结构域的 Nogo 受体相互作用蛋白 1（LINGO-1）是中枢神经系统（CNS）特异性跨膜蛋白，选择性表达于神经元和少突胶质细胞，是 CNS 损伤和疾病中轴突再生和髓鞘形成的有效负调节剂。尽管越来越多的证据表明 LINGO-1 拮抗在 CNS 损伤中改善了轴突再生和神经功能，但 LINGO-1 在神经根撕脱中的可能作用仍未被发现。在这项研究中，描述了一种使用编码 LINGO-1 短发夹干扰 RNA（shRNA）的慢病毒载体通过 Pluronic F-127（PF-127）水凝胶进行的 LINGO-1 敲低策略，该策略在臂丛撕脱（BPA）后使用。我们提供的证据表明，在 BPA 后立即再植入，用 PF-127 包裹的 LINGO-1 shRNA 慢病毒载体移植可挽救受损的运动神经元，增强轴突生长和髓鞘形成，重建运动终板，促进终末肌肉的再神经支配，促进血管生成，并促进撕脱前肢的恢复。总之，这些数据表明，凝胶支架递送 LINGO-1 shRNA 可能是神经根撕脱的一种潜在治疗方法。
影响陈述
在这项研究中，我们尝试将慢病毒（LV）/富含亮氨酸重复和免疫球蛋白样结构域的 Nogo 受体相互作用蛋白 1（LINGO-1）-短发夹干扰 RNA（shRNA）封装在 Pluronic F-127（PF-127）水凝胶中，移植到臂丛撕脱（BPA）-再植入模型中。我们发现，LV/LINGO-1 shRNA 的给药促进神经元存活和轴突再生，减轻肌肉萎缩和运动终板（MEP）丧失，增强新血管生成，并促进 BPA 大鼠的功能恢复。与单独应用 LV/LINGO-1 shRNA 相比，共移植 LV/LINGO-1 shRNA 和凝胶增强了存活促进作用、轴突生长和血管生成。我们的研究提供的证据表明，PF-127 递送的 LV/LINGO-1 shRNA 代表了一种修复 BPA 的新治疗策略。
