Donor age dependent graft development and recovery in a rat model of Huntington's disease: Histological and behavioral analysis

Abstract

Neural cell replacement therapy using fetal striatal cells has provided evidence of disease modification in clinical trials in Huntington's disease (HD) patients, although the results have been inconsistent. One of the contributing factors to the variable outcome could be the different capacity of transplanted cells derived from the primordial striatum to proliferate and maturate into striatal projection neurons. Based on the rodent lesion model of HD, the current study investigated how intrastriatal-striatal grafts from variable aged donors develop in vivo and how they influence functional recovery.Young adult female Sprague-Dawley rats were lesioned unilaterally in the dorso-striatum with quinolinic acid (0.12M) and transplanted 14 days later with single cell suspension grafts equivalent of one whole ganglionic eminence (WGE) from donors of embryonic developmental age E13, E14, or E15; animals with or without striatal lesion served as controls. All animals were tested on the Cylinder and the Corridor tests, as well as on apomorphine-induced rotation at baseline, post-lesion/pre-grafting, and at 6 and 10 weeks post-grafting. A week prior to perfusion, a sub-group in each grafted group received fluorogold injections into the ipsilateral globus pallidus to study graft efferent projections. In summary, the data demonstrates that the age of the embryonic donor tissue has an impact on both the graft mediated functional recovery, and on the in vivo cellular composition of the striatal transplant. E13 tissue grafts gave the best overall outcome indicating that WGE from different donor ages have different potential to promote functional recovery. Understanding the stages and process in rodent striatal development could improve tissue selection in clinical trials of cell therapy in HD.