Medium- to long-term survival and functional examination of human iPSC-derived retinas in rat and primate models of retinal degeneration
Medium- to long-term survival and functional examination of human iPSC-derived retinas in rat and primate models of retinal degeneration
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DOI：
10.1016/j.ebiom.2018.11.028
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发表时间：
2019-01-01
期刊：
影响因子：
11.1
通讯作者：
Mandai, Michiko
中科院分区：
文献类型：
--
作者：
Tu, Hung-Ya;Watanabe, Takehito;Mandai, Michiko
背景：我们以前曾报道，异种移植的人胚胎干细胞来源的视网膜能够在免疫缺陷的视网膜变性啮齿动物模型中成熟，类似于使用小鼠IPSC来源的视网膜进行异体移植。后者中的光感受器发育外节并与宿主双极细胞形成突触，驱动宿主视网膜神经节细胞的光反应。从临床应用的角度出发，进一步证实了人iPSC-视网膜在大鼠和猴视网膜变性模型中成熟的能力。方法：将人IPSC-视网膜移植到视紫红质突变体SD-Foxn1 TG(S334ter)3LavRrrc裸鼠和2只激光诱导的光感受器变性的猴体内。用免疫组织化学方法检测移植物的成熟度，并通过多电极阵列(MEA)记录大鼠视网膜和猴的视觉引导眼跳(VGS)来检测移植物的功能。结果：HiPSC-视网膜移植物中大量成熟的光感受器在宿主视网膜中存活至少5个月(大鼠)至2年以上(猴子)。在7只移植的大鼠视网膜中，有4只在移植区域检测到RGC光反应。该猴子移植1.5年后的VGS表现也表明光感觉有轻微的恢复。解释：我们的结果支持HiPSC来源的视网膜有能力临床应用于视网膜变性的移植治疗，尽管在目前的模型中观察到的光反应并不能与退化宿主视网膜的残留功能最终区分开来。功能分析可能会使用其他更先进的视网膜变性模型来进一步阐述。(C)2018年作者。爱思唯尔出版公司(Elsevier B.V.)
Background: We have previously reported that xeno-transplanted human ESC-derived retinas are able to mature in the immunodeficient retinal degeneration rodent models, similar to allo-transplantations using mouse iPSC-derived retina. The photoreceptors in the latter developed outer segments and formed synapses with host bipolar cells, driving light responses of host retinal ganglion cells. In view of clinical application, here we further confirmed the competency of human iPSC-derived retina (hiPSC-retina) to mature in the degenerated retinas of rat and monkey models.Methods: Human iPSC-retinas were transplanted in rhodopsin mutant SD-Foxn1 Tg(S334ter)3LavRrrc nude rats and two monkeys with laser-induced photoreceptor degeneration. Graft maturation was studied by immunohistochemistry and its function was examined by multi-electrode array (MEA) recording in rat retinas and visually guided saccade (VGS) in a monkey.Findings: A substantial amount of mature photoreceptors in hiPSC-retina graft survived well in the host retinas for at least 5 months (rat) to over 2 years (monkey). In 4 of 7 transplanted rat retinas, RGC light responses were detected at the grafted area. A mild recovery of light perception was also suggested by the VGS performance 1.5 years after transplantation in that monkey.Interpretation: Our results support the competency of hiPSC-derived retinas to be clinically applied for transplantation therapy in retinal degeneration, although the light responses observed in the present models were not conclusively distinguishable from residual functions of degenerating host retinas. The functional analysis may be further elaborated using other models with more advanced retinal degeneration. (c) 2018 The Authors. Published by Elsevier B.V.