Does epigenetic memory influence the differentiation of medium spiny neurons from fetal (360G-Wellcome-105215_Z_14_Z)

Huntington’s disease (HD) is a neurodegenerative disorder characterised by focal loss of medium spiny striatal neurons (MSNs), positioning it as an attractive model for developing cell replacement therapies (CRTs). Induced human pluripotent stem cells (hiPSc) are potential donor cells, for CRT in HD, but a key requirement for fully functional grafts is differentiation into "authentic" MSNs. Previous work in the host lab indicated that hiPSc lines derived from developing striatum (whole ganglionic eminence: WGE) demonstrate an increased propensity to differentiate back into MSNs, compared to non-striatal or nonneural derived hiPSc lines. This may be due to retained epigenetic profiles, thus I will establish (i) whether WGE-derived hiPSc lines retain epigenetic characteristics of the source tissue, and (ii) the effect of this on directed differentiation and functional recovery in a HD animal model. New hiPSc lines will be derived from the developing striatum, cortex, cerebellum, and skin of the same fetus and directed towards a MSN fate. In vitro immunocytochemical and electrophysiological analysis will be followed by grafting of optimised lines with subsequent behavioural and histological analysis. The global gene expression profiles will be determined at key stages using the HumanHT-12 v4 Expression BeadChip to characterise epigenetic differences.