Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells
Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells
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DOI：
10.1073/pnas.95.7.3978
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发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Aguayo, AJ
中科院分区：
文献类型：
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作者：
Di Polo, A;Aigner, LJ;Aguayo, AJ
在这项研究中，我们证明：（i）将含有脑源性神经营养因子（BDNF）基因（Ad.BDNF）的腺病毒（Ad）载体注射到成年大鼠的玻璃体腔中，导致 Muller 细胞选择性转基因表达； (ii) 在体外，感染 Ad.BDNF 的高等细胞会分泌 BDNF，从而增强神经元的存活； (iii) 在体内，Ad 介导的 Muller 细胞表达功能性 BDNF，暂时延长了轴突型视网膜神经节细胞 (RGC) 的存活时间； 16 天后，用 Ad.BDNF 治疗的轴突损伤视网膜显示，与对照视网膜相比，存活的 RGC 增加了 4.5 倍； (iv)持续大约10天的BDNF转基因瞬时表达，通过免疫抑制可以延长至少30天，并且这种Ad介导的BDNF仍然具有生物活性，(v)受感染的Muller细胞持续表达BDNF不会进一步增强受损RGC的存活，表明这种神经营养蛋白对RGC存活的影响受到以下因素的限制： 视神经横断后 10-16 天内病变引起的变化而不是 BDNF 的可用性。因此，Ad 转导的 Muller 细胞是一种将 BDNF 持续递送至急性损伤的 RGC 的新途径。由于这些细胞跨越了视网膜的整个厚度，Ad 介导的 Muller 细胞基因递送也可能有助于影响光感受器和其他视网膜神经元。
In this study, we demonstrate that: (i) injection of an adenovirus (Ad) vector containing the brain-derived neurotrophic factor (BDNF) gene (Ad.BDNF) into the vitreous chamber of adult rats results in selective transgene expression by Muller cells; (ii) in vitro, higher cells infected with Ad.BDNF secrete BDNF that enhances neuronal survival; (iii) in viva, Ad-mediated expression of functional BDNF by Muller cells, temporarily extends the survival of axotomized retinal ganglion cells (RGCs); 16 days after axotomyl injured retinas treated with Ad.BDNF showed a 4.5-fold increase in surviving RGCs compared with control retinas; (iv) the transient expression of the BDNF transgene, which lasted approximate to 10 days, call be prolonged with immunosuppression for at least 30 days, and such Ad-mediated BDNF remains biologically active, (v) persistent expression of BDNF by infected Muller cells does not further enhance the survival of injured RGCs, indicating that the effect of this neurotrophin on RGC survival is limited by changes induced by the lesion within 10-16 days after optic nerve transection rather than the availability of BDNF. Thus, Ad-transduced Muller cells are a novel pathway for sustained delivery of BDNF to acutely-injured RGCs, Because these cells span the entire thickness of the retina, Ad-mediated gene delivery to Muller cells may also be useful to influence photoreceptors and other retinal neurons.