Background Cell replacement therapy (CRT) is a potential therapeutic intervention for Huntington’s disease (HD). A growing body of evidence has indicated that motoric and cognitive recovery can be achieved following transplantation of functional striatal precursor cells into the damaged animal and human striatum. However, currently no one cell source is suitable for widespread and long term clinical use. Human induced pluripotent stem cells (iPSC) can theoretically be generated from any viable human cells and are logistically suitable for CRT. Additionally, previous work has demonstrated iPSCs may retain former epigenetic mechanisms that control gene expression and promote a return to previously held cell fate. If generated from suitable tissue sources, this ‘epigenetic memory’ may facilitate improved generation of functional striatal precursor cells compared to other logistically suitable cell sources.
Aim This work aims to identify the potential of fetal striatal-derived iPSC epigenetic memory to determine functional MSN differentiation, and to explore the potential of this cell source to induce recovery in an animal model of HD.
Experimental plans To achieve these aims we have generated iPSC lines from fetal striatal, cortical and fibroblast tissues. These lines are currently being characterised in vitro for pluripotency, and MSN generation potential, directly comparing the different tissue derived iPSC lines with embryonic stem cell (ESC) controls. We intend to characterise DNA methylation profiles of each iPSC line across the induction and differentiation process, to gain insight into the epigenetic profiles at key stages. Lastly, in vivo graft characterisation and behavioural assessments will determine if the presence of epigenetic memory in fetal striatal-derived iPSCs directed towards a neural precursor fate can be used to generate better functioning grafts than those derived from ESC and primary fetal cells.
- CELL REPLACEMENT THERAPY
- EPIGENETIC MEMORY