Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Handb Exp Pharmacol. 2023;281:83-102. doi: 10.1007/164_2023_642.
The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) provides an extraordinary opportunity to study the development of RGCs as well as cellular mechanisms underlying their degeneration in optic neuropathies. In the past several years, multiple approaches have been established that allow for the generation of RGCs from hPSCs, with these methods greatly improved in more recent studies to yield mature RGCs that more faithfully recapitulate phenotypes within the eye. Nevertheless, numerous differences still remain between hPSC-RGCs and those found within the human eye, with these differences likely explained at least in part due to the environment in which hPSC-RGCs are grown. With the ultimate goal of generating hPSC-RGCs that most closely resemble those within the retina for proper studies of retinal development, disease modeling, as well as cellular replacement, we review within this manuscript the current effective approaches for the differentiation of hPSC-RGCs, as well as how they have been applied for the investigation of RGC neurodegenerative diseases such as glaucoma. Furthermore, we provide our opinions on the characteristics of RGCs necessary for their use as effective in vitro disease models and importantly, how these current systems should be improved to more accurately reflect disease states. The establishment of characteristics in differentiated hPSC-RGCs that more effectively mimic RGCs within the retina will not only enable their use as effective models of RGC development, but will also create a better disease model for the identification of mechanisms underlying the neurodegeneration of RGCs in disease states such as glaucoma, further facilitating the development of therapeutic approaches to rescue RGCs from degeneration in disease states.
从人类多能干细胞（hPSCs）中衍生出视网膜神经节细胞（RGCs）的能力为研究 RGCs 的发育以及在视神经病变中导致其退化的细胞机制提供了极好的机会。在过去的几年中，已经建立了多种方法，可以从 hPSCs 中产生 RGCs，这些方法在最近的研究中得到了极大的改进，以产生更成熟的 RGCs，更忠实地再现眼睛内的表型。然而，hPSC-RGCs 与在人眼中发现的 RGCs 之间仍然存在许多差异，这些差异至少部分归因于 hPSC-RGCs 生长的环境。为了生成最接近人眼中 RGCs 的 hPSC-RGCs，以便对视网膜发育、疾病建模以及细胞替代进行适当的研究，我们在本文中回顾了当前有效分化 hPSC-RGCs 的方法，以及它们如何应用于研究 RGC 神经退行性疾病，如青光眼。此外，我们还就 RGCs 的特征发表了意见，这些特征对于将其用作有效的体外疾病模型是必要的，重要的是，如何改进这些当前的系统，以更准确地反映疾病状态。分化的 hPSC-RGCs 中建立的更有效地模拟视网膜内 RGCs 的特征，不仅将使它们能够有效地作为 RGC 发育的模型，还将为确定青光眼等疾病状态下 RGC 神经退行性的机制提供更好的疾病模型，进一步促进治疗方法的发展，以防止疾病状态下 RGC 的退化。
