Abstract
BackgroundCell 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. ResultsWe 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.
Highlights
Huntington disease (HD) is a neurodegenerative condition associated with motor, cognitive and psychiatric symptoms [1]
Using developmental principles previously applied to hESCs for STR differentiation [25À27], we found that these human WGE (hWGE) induced pluripotent stem cells (iPSC) differentiate into neurons expressing a range of medium spiny neurons (MSNs) markers, including FOXP1, CTIP2 and DARPP-32, similar to what is achievable with hESCs
We examined the methylome of hWGE iPSCs and hESCs exposed to the STR differentiation protocol and demonstrated significant demethylation at CpG sites associated with STR genes in both, consistent with the current understanding of the developmental role of methylation [28]
Summary
Huntington disease (HD) is a neurodegenerative condition associated with motor, cognitive and psychiatric symptoms [1]. Intra-STR allografts of MSN progenitors derived from primary fetal whole ganglionic eminence (WGE), the primordial striatum, have been shown to express DARPP-32 (PPP1R1B), the principal marker of MSNs, and bring about motor and cognitive functional recovery in HD rat models. Expression of DARPP-32 donor-derived cells, along with functional improvements, has been observed in xenografts of human WGE (hWGE) in the HD rat striatum [4]. 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. IPSCs derived from human WGE show promise as a donor source for CRT for HD
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