Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montreal (IRCM), Montreal, QC, Canada.
Molecular Biology Program, Université de Montréal, Montreal, QC, Canada.
Front Neural Circuits. 2017 Dec 19;11:105. doi: 10.3389/fncir.2017.00105. eCollection 2017.
Retinal degenerative diseases, which lead to the death of rod and cone photoreceptor cells, are the leading cause of inherited vision loss worldwide. Induced pluripotent or embryonic stem cells (iPSCs/ESCs) have been proposed as a possible source of new photoreceptors to restore vision in these conditions. The proof of concept studies carried out in mouse models of retinal degeneration over the past decade have highlighted several limitations for cell replacement in the retina, such as the low efficiency of cone photoreceptor production from stem cell cultures and the poor integration of grafted cells in the host retina. Current protocols to generate photoreceptors from stem cells are largely based on the use of extracellular factors. Although these factors are essential to induce the retinal progenitor cell (RPC) fate from iPSCs/ESCs, developmental studies have shown that RPCs alter fate output as a function of time (i.e., their temporal identity) to generate the seven major classes of retinal cell types, rather than spatial position. Surprisingly, current stem cell differentiation protocols largely ignore the intrinsic temporal identity of dividing RPCs, which we argue likely explains the low efficiency of cone production in such cultures. In this article, we briefly review the mechanisms regulating temporal identity in RPCs and discuss how they could be exploited to improve cone photoreceptor production for cell replacement therapies.
视网膜退行性疾病导致视杆和视锥光感受器细胞死亡，是全球遗传性视力丧失的主要原因。诱导多能干细胞或胚胎干细胞（iPSC/ESC）被提议作为一种可能的新光感受器来源，以恢复这些情况下的视力。在过去十年中，对视网膜退行性变的小鼠模型进行的概念验证研究强调了视网膜细胞替代的几个局限性，例如从干细胞培养物中产生视锥细胞的效率低，以及移植细胞在宿主视网膜中的整合不良。目前从干细胞产生光感受器的方案在很大程度上基于细胞外因子的使用。尽管这些因子对于从 iPSC/ESC 诱导视网膜祖细胞（RPC）命运是必需的，但发育研究表明，RPC 会随着时间的推移（即它们的时间身份）改变命运输出，以产生七类主要的视网膜细胞类型，而不是空间位置。令人惊讶的是，目前的干细胞分化方案在很大程度上忽略了分裂 RPC 的内在时间身份，我们认为这可能解释了为什么在这种培养物中产生视锥细胞的效率低。在本文中，我们简要回顾了调节 RPC 时间身份的机制，并讨论了如何利用这些机制来提高用于细胞替代疗法的视锥细胞产生效率。
