Bartley, O. J. M.; Vinh, N.-N.; Lelos, M.; Williams, N. M.; Precious, S. V.; Rosser, A. E.

Induced pluripotent stem cells (iPSCs) have previously been shown to retain some of the epigenetic features associated with the tissues from which they were derived, which in turn can help the iPSCs to differentiate towards similar cell fates. Here we investigate whether human iPSCs (hiPSC) derived from the lateral ganglionic eminence (LGE) retain sufficient epigenetic features of their original tissue to enhance their capacity to differentiate into striatal medium spiny neurons (MSN) compared to isogenic controls. We identify a subtle methylation signature within these isogenic hiPSCs, and observe they have varying capacity between lines to produce MSN-like cells and their subtypes. We directly compare these cells to authentic LGE derived MSNs and identify large differences in DNA methylation between these populations. Using single cell RNAseq, we also find subpopulations that do not reflect the transcriptional profile of authentic MSNs. While we did observe some potential epigenetic \'\'benefits\'\' within our LGE derived hiPSC-MSNs (e.g. reduced hypomethylation of off-target pathways and reduced expression of off-target genes), we did not observe an improved propensity to differentiate towards a D1 or D2 MSN-like fate. Overall, this work highlights that pluripotent stem cells are unique in their individual capacity for differentiation, that subtle differences between cell lines can have far reaching effects on the final cell product, and that while hPSC-MSNs can model many aspects of MSN development, there are still epigenetic and transcriptional differences that limit the full recapitulation of the authentic LGE-derived MSN phenotype.