Ming Ming, Li Xuping, Fan Xiaolan, Yang Dehua, Li Liang, Chen Sheng, Gu Qing, Le Weidong
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China.
J Transl Med. 2009 Jun 28;7:53. doi: 10.1186/1479-5876-7-53.
New strategies for the treatment of Parkinson's disease (PD) are shifted from dopamine (DA) replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE) cells as substitution for degenerated dopaminergic (DAergic) neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA.
We evaluated the protective effects of conditioned medium (CM) from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA)- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR).
We report here: (1) CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2) cultured RPE cells express L-dopa decarboxylase (DDC) and synthesize DA; (3) RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4) GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues.
These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.
帕金森病（PD）的治疗新策略已从多巴胺（DA）替代转向黑质纹状体系统的再生或修复。一种使用人视网膜色素上皮（RPE）细胞替代退化的多巴胺能（DAergic）神经元的细胞疗法已被开发出来，并在PD的临床治疗中显示出有前景的前景，但该疗法的确切机制尚未完全阐明。在本研究中，我们调查了这种疗法的有益效果是否与RPE细胞的营养特性及其合成DA的能力有关。
我们评估了培养的RPE细胞条件培养基（CM）对DAergic细胞抗6-羟基多巴胺（6-OHDA）和鱼藤酮诱导的神经毒性的保护作用，并测定了RPE细胞释放的胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）水平。我们还测量了DA的合成和释放。最后，我们将微载体-RPE细胞移植到6-OHDA损伤的大鼠中，并观察阿扑吗啡诱导的旋转（AIR）的改善情况。
我们在此报告：（1）RPE细胞的CM可分泌营养因子GDNF和BDNF，并保护DAergic神经元免受6-OHDA和鱼藤酮诱导的细胞损伤；（2）培养的RPE细胞表达L-多巴脱羧酶（DDC）并合成DA；（3）附着在微载体上的RPE细胞可在宿主纹状体中存活，并改善PD的6-OHDA损伤动物模型中的AIR；（4）在RPE细胞移植组织中发现GDNF和BDNF水平显著更高。
这些发现表明RPE细胞具有分泌GDNF和BDNF以及合成DA的能力，这可能有助于RPE细胞移植在PD中的治疗效果。
