Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model.
Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model.
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DOI：
10.1523/jneurosci.2841-12.2012
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发表时间：
2012-11-07
期刊：
影响因子：
--
通讯作者：
Gillies MC
中科院分区：
文献类型：
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作者：
Shen W;Fruttiger M;Zhu L;Chung SH;Barnett NL;Kirk JK;Lee S;Coorey NJ;Killingsworth M;Sherman LS;Gillies MC
穆勒细胞是视网膜的主要神经胶质细胞，具有对视网膜稳态至关重要的多种功能，但穆勒神经胶质细胞功能障碍对视网膜疾病的影响仍然很大程度上未知。我们开发了一种转基因模型，使用视黄醛结合蛋白 1 基因的部分调控区进行条件性 Müller 细胞消融，并在成年小鼠中研究了原发性 Müller 细胞功能障碍的后果。我们发现选择性消融穆勒细胞会导致光感受器凋亡、血管毛细血管扩张、血-视网膜屏障破坏以及随后的视网膜内新生血管形成。这些变化伴随着视网膜功能受损以及血管内皮生长因子-A (VEGF-A) 和色素上皮衍生因子之间的不平衡。玻璃体内注射睫状神经营养因子可抑制光感受器损伤，但对血管病变没有影响。相反，抑制 VEGF-A 活性可减少血管渗漏，但不能保护光感受器。我们的研究结果表明，穆勒胶质细胞缺乏可能是视网膜疾病中视网膜神经元和血管病变的重要上游原因。可能需要联合神经保护和抗血管生成疗法来治疗视网膜疾病和与神经胶质功能障碍相关的中枢神经系统其他部分的穆勒细胞缺陷。
Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium derived factor. Intravitreal injection of cilliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the central nervous system associated with glial dysfunction.