GDNF-Enhanced Axonal Regeneration and Myelination Following Spinal Cord Injury is Mediated by Primary Effects on Neurons

我们先前研究表明胶质细胞源性神经营养因子(GDNF)联合施万细胞移植能促进脊髓损伤后轴突再生和髓鞘形成。然而,GDNF介导这一过程的细胞靶点尚不清楚。在此,我们报道了GDNF可增加在体再生轴突的数目和直径,并促进体外背根神经节神经元的轴突向外生长,提示GDNF对神经元有直接作用。在施万细胞-背根神经节神经元共培养下,GDNF显著增加施万细胞生成的髓鞘数目;GDNF处理对孤立培养的施万细胞增殖无作用,但可促进已与神经轴突有突触联系的施万细胞增殖;GDNF可增加孤立施万细胞中分子量为140kDa的神经细胞黏附分子(NCAM)的表达,但对黏附分子L1表达或神经营养因子NGF、NT3及BDNF分泌没有影响。总之,这些结果支持假设:GDNF提高轴突再生和施万细胞髓鞘形成主要是通过GDNF对神经元的直接作用介导的,并且提示GDNF联合施万细胞移植可能是促进脊髓损伤后轴突再生和髓鞘形成的有效策略之一。

We previously demonstrated that coadministration of glial cell line-derived neurotrophic factor（GDNF） with grafts of Schwann cells（SCs） enhanced axonal regeneration and remyelination following spinal cord injury（SCI）. However, the cellular target through which GDNF mediates such actions was unclear. Here,we report that GDNF enhanced both the number and caliber of regenerated axons in vivo and increased neurite outgrowth of dorsal root ganglion neurons（DRGN） in vitro,suggesting that GDNF has a direct effect on neurons. In SC- DRGN coculture,GDNF significantly increased the num- ber of myelin sheaths produced by SCs. GDNF treatment had no effect on the proliferation of isolated SCs but enhanced the proliferation of SCs already in contact with axons. GDNF increased the expression of the 140 kDa neural cell adhesion mole- cule（NCAM） in isolated SCs but not their expression of the adhesion molecule 1.1 or the secretion of the neurotrophins NGF, NT3,or BDNF. Overall,these results support the hypothesis that GDNF enhanced axonal regeneration and SC myeli- nation is mediated mainly through a direct effect of GDNF on neurons. They also suggest that the combination of GDNF ad- ministration and SC transplantation may represent an effective strategy to promote axonal regeneration and myelin formation after injury in the spinal cord. @ 2009 Wiley Liss, Inc.