Direct Comparison of Rat- and Human-Derived Ganglionic Eminence Tissue Grafts on Motor Function

Abstract

Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.

Transplantation in HD: Are We Transplanting the Right Cells?

“…In agreement with these earlier studies, we too see an improvement in apomorphine-induced rotations using human foetal WGE at 8-week post-conception [38]. Furthermore, improvement was also seen in the vibrissae-evoked forepaw placing test, as well as stabilisation over time in the adjusting steps test [38].…”

“…Furthermore, improvement was also seen in the vibrissae-evoked forepaw placing test, as well as stabilisation over time in the adjusting steps test [38]. Together these studies build on the histological assessments of cell survival and integration.…”

“…In the studies of human foetal tissue transplants in animal models described above, the behavioural effects reported have been limited to drug-induced rotations, vibrissae-evoked touch test and adjusting steps test, and so far no effect has been reported on the paw-reaching test [35][36][37][38]. However, to date, neither the approach of additional training to allow transplanted animals to re-learn a task post-transplantation, and learn to use the graft, nor the environmental enrichment strategy has been applied to human foetal striatal transplant studies.…”

“…This has not been systematically investigated to date in any one, single study for human foetal samples. Thus, it is necessary to draw what we can from the published literature in which a range of ages from 6-to 14-week gestation has been used [35][36][37][38]. It has been shown that human foetal WGE cells harvested at 7-to 9-week post-conception [37] and also at 14-week post-conception [36] are able to ameliorate the apomorphine-induced deficits seen in animals having received unilateral excitotoxic striatal lesions, which mimic the pattern of cell loss seen in HD.…”

“…It is critical that the questions raised above are not dismissed as new cell sources are investigated, and one key step in preclinical validation of these alternatives will be to compare them to primary foetal tissue transplants. One important consideration relates to the functional readout from such studies, especially given the limited data thus far generated from transplants of human foetal tissue [35][36][37][38]; some rodent studies have highlighted the plasticity of striatal grafts, which can have implications on functional effects post-transplantation [40][41][42][43][44]. It has been shown that animals post-transplantation need to 're-learn' a task that had been well established prior to induction of the lesion, using the 9-hole box operant chamber [40].…”