Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury.
Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury.
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DOI：
10.1093/brain/aww039
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Bradbury EJ
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作者：
Bartus K;Galino J;James ND;Hernandez-Miranda LR;Dawes JM;Fricker FR;Garratt AN;McMahon SB;Ramer MS;Birchmeier C;Bennett DL;Bradbury EJ
脊髓损伤后自发性髓鞘再生主要由来源不明的雪旺细胞介导。Bartus等人的研究表明，神经调节蛋白-1促进脊髓前体细胞向pns样雪旺细胞分化，使中枢轴突再髓鞘化，促进功能恢复。以神经调节蛋白-1系统为靶点可促进内源性再生过程。脊髓损伤后自发性髓鞘再生主要由来源不明的雪旺细胞介导。Bartus等人的研究表明，神经调节蛋白-1促进脊髓前体细胞向pns样雪旺细胞分化，使中枢轴突再髓鞘化，促进功能恢复。以神经调节蛋白-1系统为靶点可促进内源性再生过程。创伤性脊髓损伤后，脊髓轴突发生急性脱髓鞘，随后出现一段时间的自发性髓鞘再生。然而，这种内源性修复反应是次优的，可能是存活轴突功能持续受损的原因。自发性髓鞘再生主要由雪旺细胞介导，其中脱髓鞘的中央轴突，特别是在背柱，与外周髓鞘相关。这些中央髓鞘再生雪旺细胞的分子控制、功能作用和起源目前尚不清楚。生长因子神经调节蛋白-1 （Nrg1，由Nrg1编码）是控制周围神经系统髓鞘形成的关键信号因子，通过ErbB酪氨酸激酶受体传递信号。在这里，我们研究了中央背柱轴突雪旺细胞介导的髓鞘再生是否需要Nrg1，以及Nrg1消融是否影响脊髓损伤后自发性髓鞘再生的程度和功能恢复。在条件消融Nrg1的挫伤成年小鼠中，我们发现脊髓内雪旺细胞缺失，背柱轴突深度脱髓鞘。少突胶质细胞再生无代偿性增加。脊髓外周输入的移除和增殖研究表明，大多数髓鞘再生雪旺细胞起源于受损脊髓。我们还研究了特异性Nrg1异构体的作用，使用突变小鼠，其中只有含有免疫球蛋白的Nrg1异构体（I型和II型）被有条件地切除，留下III型Nrg1完整。我们发现免疫球蛋白Nrg1亚型在脊髓损伤后雪旺细胞介导的中枢轴突再髓鞘形成中是不可缺少的。当检查功能影响时，与受伤的对照组相比，全局Nrg1和免疫球蛋白特异性Nrg1突变体都表现出自发运动恢复的减少，尽管全局Nrg1突变体在需要协调、平衡和本体感觉的测试中受损更大。此外，电生理评估显示，Nrg1突变体的背柱轴突传导严重受损（雪旺细胞介导的髓鞘再生被阻止），但免疫球蛋白特异性突变体没有（雪旺细胞介导的髓鞘再生保持完整），这提供了强有力的证据，证明Nrg1突变小鼠背柱中观察到的深度脱髓鞘表型与传导失败有关。我们的数据为脊髓损伤后内源性再生过程提供了新的机制见解，表明Nrg1信号调节中枢轴突髓鞘再生和功能修复，并驱动中枢前体细胞向外周神经系统样雪旺细胞的反分化，在损伤后脊髓轴突髓鞘再生。因此，可以利用Nrg1系统的操纵来增强脊髓损伤和其他具有脱髓鞘病理的中枢神经系统疾病后的自发修复。
Spontaneous remyelination after spinal cord injury is mediated largely by Schwann cells of unknown origin. Bartus et al. show that neuregulin-1 promotes differentiation of spinal cord-resident precursor cells into PNS-like Schwann cells, which remyelinate central axons and promote functional recovery. Targeting the neuregulin-1 system could enhance endogenous regenerative processes. Spontaneous remyelination after spinal cord injury is mediated largely by Schwann cells of unknown origin. Bartus et al. show that neuregulin-1 promotes differentiation of spinal cord-resident precursor cells into PNS-like Schwann cells, which remyelinate central axons and promote functional recovery. Targeting the neuregulin-1 system could enhance endogenous regenerative processes. Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of surviving axons. Spontaneous remyelination is largely mediated by Schwann cells, where demyelinated central axons, particularly in the dorsal columns, become associated with peripheral myelin. The molecular control, functional role and origin of these central remyelinating Schwann cells is currently unknown. The growth factor neuregulin-1 (Nrg1, encoded by NRG1) is a key signalling factor controlling myelination in the peripheral nervous system, via signalling through ErbB tyrosine kinase receptors. Here we examined whether Nrg1 is required for Schwann cell-mediated remyelination of central dorsal column axons and whether Nrg1 ablation influences the degree of spontaneous remyelination and functional recovery following spinal cord injury. In contused adult mice with conditional ablation of Nrg1, we found an absence of Schwann cells within the spinal cord and profound demyelination of dorsal column axons. There was no compensatory increase in oligodendrocyte remyelination. Removal of peripheral input to the spinal cord and proliferation studies demonstrated that the majority of remyelinating Schwann cells originated within the injured spinal cord. We also examined the role of specific Nrg1 isoforms, using mutant mice in which only the immunoglobulin-containing isoforms of Nrg1 (types I and II) were conditionally ablated, leaving the type III Nrg1 intact. We found that the immunoglobulin Nrg1 isoforms were dispensable for Schwann cell-mediated remyelination of central axons after spinal cord injury. When functional effects were examined, both global Nrg1 and immunoglobulin-specific Nrg1 mutants demonstrated reduced spontaneous locomotor recovery compared to injured controls, although global Nrg1 mutants were more impaired in tests requiring co-ordination, balance and proprioception. Furthermore, electrophysiological assessments revealed severely impaired axonal conduction in the dorsal columns of global Nrg1 mutants (where Schwann cell-mediated remyelination is prevented), but not immunoglobulin-specific mutants (where Schwann cell-mediated remyelination remains intact), providing robust evidence that the profound demyelinating phenotype observed in the dorsal columns of Nrg1 mutant mice is related to conduction failure. Our data provide novel mechanistic insight into endogenous regenerative processes after spinal cord injury, demonstrating that Nrg1 signalling regulates central axon remyelination and functional repair and drives the trans-differentiation of central precursor cells into peripheral nervous system-like Schwann cells that remyelinate spinal axons after injury. Manipulation of the Nrg1 system could therefore be exploited to enhance spontaneous repair after spinal cord injury and other central nervous system disorders with a demyelinating pathology.