Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration.
Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration.
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DOI：
10.1016/j.stemcr.2017.04.030
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
Ali RR
中科院分区：
文献类型：
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作者：
Kruczek K;Gonzalez-Cordero A;Goh D;Naeem A;Jonikas M;Blackford SJI;Kloc M;Duran Y;Georgiadis A;Sampson RD;Maswood RN;Smith AJ;Decembrini S;Arsenijevic Y;Sowden JC;Pearson RA;West EL;Ali RR
介导日光视觉的视锥光感受器的丧失是失明的主要原因，通过移植进行细胞替代提供了一种有希望的治疗策略。在这里，我们的特点锥分化视网膜来源于小鼠胚胎干细胞（mESCs）。与体内发育相似，祖细胞标志物表达的时间模式之后是早期甲状腺激素受体β2阳性前体的分化，随后是表现出视锥细胞特异性光转导相关蛋白的光感受器。我们建立了阶段特异性抑制Notch途径增加视锥细胞分化，而视黄酸信号调节视锥成熟，与它们在体内的作用相当。MESC衍生的视锥细胞可以大量分离并移植到成年小鼠眼中，显示出在终末期视网膜变性模型Aipl 1 −/−小鼠的视网膜下腔中存活和成熟的能力。总之，这项工作确定了一个强大的，可再生的细胞来源，通过纯化的细胞悬液移植锥更换。在mESC视网膜类器官中有效形成视锥光感受器前体Notch信号传导限制视锥细胞分化的时间能力视锥成熟需要降低的视黄酸浓度移植到晚期视网膜变性模型中的视锥存活并成熟Ali和同事表征了mESC视网膜类器官中视锥光感受器的分化，显示了大量的定向视锥前体。它们的分化受Notch途径、Nrl和Nr 2 e3的表达以及高浓度的视黄酸负调控。分离并移植到严重退化的视网膜中，这些视锥前体存活并表达高级成熟的标记。
The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor β2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction-related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1−/− mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation. Cone photoreceptor precursors form efficiently in mESC retinal organoids Notch signaling limits temporal competence for cone cell differentiation Reduced retinoic acid concentrations are required for cone maturation Cones transplanted into a model of advanced retinal degeneration survive and mature Ali and colleagues characterize the differentiation of cone photoreceptors in mESC retinal organoids, showing substantial numbers of committed cone precursors. Their differentiation is negatively regulated by the Notch pathway, expression of Nrl and Nr2e3, and high concentrations of retinoic acid. Isolated and transplanted into a severely degenerated retina, these cone precursors survive and express markers of advanced maturation.