Daylight Vision Repair by Cell Transplantation
Daylight Vision Repair by Cell Transplantation
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DOI：
10.1002/stem.1824
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发表时间：
2015-01-01
期刊：
影响因子：
5.2
通讯作者：
Ader, Marius
中科院分区：
文献类型：
--
作者：
Santos-Ferreira, Tiago;Postel, Kai;Ader, Marius
人类日光视力依赖于视锥光感受器，其退化会导致视力障碍和失明，如在多种眼部疾病中观察到的那样，包括年龄相关性黄斑变性、视锥杆营养不良或晚期视网膜色素变性，且无法治愈。小鼠视网膜的临床前细胞替代方法一直专注于视杆细胞营养不良，因为可从视杆细胞为主的小鼠视网膜获得足够的供体材料，从而导致视锥细胞变性的治疗方案的开发尚未得到充分研究。因此，通过将神经视网膜亮氨酸拉链缺陷（Nrl（-/-））小鼠与普遍存在的绿色荧光蛋白（GFP）报告系杂交，产生了双转基因tg（Nrl（-/-）；aGFP）小鼠，从而产生了丰富且可追踪的供体锥状光感受器来源。在 Nrl(-/-) 视网膜中，所有视杆细胞都转化为表达 CD73 的锥状光感受器，允许在移植到成年野生型、仅视锥细胞 (Nrl(-/-)) 或视锥光感受器功能丧失 1 (Cpfl1) 小鼠的视网膜下空间之前，通过基于 CD73 的磁激活细胞分选来富集它们。供体细胞正确整合到宿主视网膜中，获得成熟的光感受器形态，表达视锥细胞特异性标记物，并存活长达6个月，并且在仅视锥细胞的Nrl(-/-)视网膜中的整合率显着增加。个体视网膜神经节细胞记录表明，视锥细胞退化小鼠在移植后恢复了明视反应，这首次表明通过成年哺乳动物视网膜细胞替代来修复日光视力的可行性。
Human daylight vision depends on cone photoreceptors and their degeneration results in visual impairment and blindness as observed in several eye diseases including age-related macular degeneration, cone-rod dystrophies, or late stage retinitis pigmentosa, with no cure available. Preclinical cell replacement approaches in mouse retina have been focusing on rod dystrophies, due to the availability of sufficient donor material from the rod-dominated mouse retina, leaving the development of treatment options for cone degenerations not well studied. Thus, an abundant and traceable source for donor cone-like photoreceptors was generated by crossing neural retina leucine zipper-deficient (Nrl(-/-)) mice with an ubiquitous green fluorescent protein (GFP) reporter line resulting in double transgenic tg(Nrl(-/-); aGFP) mice. In Nrl(-/-) retinas, all rods are converted into cone-like photoreceptors that express CD73 allowing their enrichment by CD73-based magnetic activated cell sorting prior transplantation into the subretinal space of adult wild-type, cone-only (Nrl(-/-)), or cone photoreceptor function loss 1 (Cpfl1) mice. Donor cells correctly integrated into host retinas, acquired mature photoreceptor morphology, expressed cone-specific markers, and survived for up to 6 months, with significantly increased integration rates in the cone-only Nrl(-/-) retina. Individual retinal ganglion cell recordings demonstrated the restoration of photopic responses in cone degeneration mice following transplantation suggesting, for the first time, the feasibility of daylight vision repair by cell replacement in the adult mammalian retina.