Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; Department of Anatomy, Faculty of Medical Science, Naresuan University, Phisanulok, Thailand.
Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK.
Cytotherapy. 2021 Feb;23(2):111-118. doi: 10.1016/j.jcyt.2020.06.001. Epub 2020 Nov 25.
Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells.
We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.
亨廷顿病（HD）的细胞替代疗法（CRT）需要能够恢复由于纹状体（STR）退化而丧失功能的 STR 祖细胞来源。真正的 STR 祖细胞可以从胎儿假定的纹状体或整个神经节隆起（WGE）中收集，但这些组织仍然不适用于广泛的临床应用，需要替代的供体来源。在这里，我们开始探索源自 WGE 的诱导多能干细胞（iPSC）是否可能保留其组织起源的表观遗传记忆，这可能增强它们分化为 STR 细胞的能力。
我们从人 WGE 生成了四个 iPSC 系，并确定它们在向 STR 表型分化的能力方面与人类胚胎干细胞相似，这可以通过关键 STR 基因的表达和去甲基化来衡量，同时保持整体不同的甲基组。最后，我们证明这些 STR 分化的 hWGE iPSC 在体外和移植到 HD 模型后均与 hWGE（即真实的 STR 组织）具有相似的特征。总体而言，源自人 WGE 的 iPSC 有望成为 HD 的 CRT 的供体来源。
