L26 A comparative study of human and mouse developing striatum for transplantation in huntington’s disease

Background Although Huntington’s disease (HD) affects multiple brain areas it has a disproportionate and early effect on the striatal medium spiny neurons (MSNs). Transplantation of developing rat MSNs, derived from embryonic day 14 (E14) whole ganglionic eminence (WGE), into a rodent lesion models of HD results in grafts that integrate into the host striatum, alleviating both motor and cognitive symptoms. The equivalent gestational period for human fetal WGE is thought to be 8–10 weeks post conception (pc), but transplants of tissue in this range are more morphologically and functionally variable. One potential explanation is that the generally accepted age range for human cells is not in fact optimal. Aims To estimate the optimal age of donor tissue for transplantation in HD, based on molecular, histological and electrophysiological comparisons of human and mouse WGE development across the period of peak MSN development. Methods We compared WGE from mouse (E12 to E16) and human (6–12 weeks pc) using QPCR, in situ hybridisation of tissue sections and in vitro immunocytochemistry for a range of known and potential striatal markers, and also plated cells for electrophysiology. Results Developmentally regulated striatal markers, such as GSX2, CTIP and FOXP1, show delayed expression in the human compared to rodent WGE, suggesting that human WGE within this age range is less developmentally mature than previously appreciated. This is supported by the findings that human WGE cells are still proliferative at 11 weeks pc and appear electrophysiologically less mature compared to the mouse cells. Conclusion These results suggest that the gestational range used to date for human WGE may be insufficiently mature for grafts to develop optimally. This information could help to identify optimal age of fetal donor tissue and act as a reference for MSN differentiation from pluripotent stem cells, but will need verification following transplantation.