Transplantation of Embryonic Cerebellar Grafts Improves Gait Parameters in Ataxic Lurcher Mice

Abstract

Hereditary cerebellar ataxias are severe diseases for which therapy is currently not sufficiently effective. One of the possible therapeutic approaches could be neurotransplantation. Lurcher mutant mice are a natural model of olivocerebellar degeneration representing a tool to investigate its pathogenesis as well as experimental therapies for hereditary cerebellar ataxias. The effect of intracerebellar transplantation of embryonic cerebellar solid tissue or cell suspension on motor performance in adult Lurcher mutant and healthy wild-type mice was studied. Brain-derived neurotrophic factor level was measured in the graft and adult cerebellar tissue. Gait analysis and rotarod, horizontal wire, and wooden beam tests were carried out 2 or 6 months after the transplantation. Higher level of the brain-derived neurotrophic factor was found in the Lurcher cerebellum than in the embryonic and adult wild-type tissue. A mild improvement of gait parameters was found in graft-treated Lurcher mice. The effect was more marked in cell suspension grafts than in solid transplants and after the longer period than after the short one. Lurcher mice treated with cell suspension and examined 6 months later had a longer hind paw stride (4.11 vs. 3.73 mm, P < 0.05) and higher swing speed for both forepaws (52.46 vs. 32.79 cm/s, P < 0.01) and hind paws (63.46 vs. 43.67 cm/s, P < 0.001) than controls. On the other hand, classical motor tests were not capable of detecting clearly the change in the motor performance. No strong long-lasting negative effect of the transplantation was seen in wild-type mice, suggesting that the treatment has no harmful impact on the healthy cerebellum.

Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice

“…In regard to the number of grafted cells, we cannot exclude that a higher amount of injected precursors could lead to motor improvement in tbl mutants. However, this study is within the range of amount of grafted cell, formerly shown to have a positive impact on motor functions (cfr Triarhou et al, 1996;Kaemmerer and Low, 1999;Babuska et al, 2015). This observation, together with results of former studies (Triarhou et al, 1996), suggests that a critical aspect linked to the lack of functional improvement in our transplantation approach may be an insufficient establishment of connections between grafted PCs and CNs.…”

“…This observation, together with results of former studies (Triarhou et al, 1996), suggests that a critical aspect linked to the lack of functional improvement in our transplantation approach may be an insufficient establishment of connections between grafted PCs and CNs. Also, grafted precursors did not impact significantly on the survival of endogenous mutant PCs, a beneficial effect generally promoted by transplantation of undifferentiated neural stem cells or mesenchymal stem cells (Li et al, 2006;Jones et al, 2010), and often associated with functional benefits (Kaemmerer and Low, 1999;Jones et al, 2010 andBabuska et al, 2015). In our approach, neuroprotective factors produced by undifferentiated precursors may have decreased soon after grafting due to precursor differentiation, therefore failing to effectively promote cell survival.…”

Transplantation and Stem Cell Therapy for Cerebellar Degenerations

“…Jones et al [18] described that transplantation of mesenchymal stem cells into the cerebellum of newborn Lurcher mice significantly improved motor performance and that grafted cells located adjacent to the Purkinje cells increased their survival rate by producing neurotrophic factors. Both solid as well as cell suspension embryonic cerebellar grafts are able to survive for 6 months in Lurchers, in similar percentages to in normal control mice [19,20]. Nevertheless, grafted cells tended to avoid Lurcher mutant cerebellum and fibre sprouting from the graft into the host cerebellar tissue was sparse (Fig.…”

“…Despite the low efficiency of embryonic cerebellar grafts in Lurcher mice under any conditions, cell suspension engraftment appears a bit more potent than solid grafts of the same origin. After embryonic cerebellar cell suspension transplantation, a mild increase of swing speed measured by automated gait analysis but not improvement of performances on the rotarod, horizontal wire and wooden beam tests have been observed in Lurcher mice [20]. However, a long period was needed for the functional effect to develop [20].…”

“…Nevertheless, grafted cells tended to avoid Lurcher mutant cerebellum and fibre sprouting from the graft into the host cerebellar tissue was sparse (Fig. 1) [19,20]. Despite the low efficiency of embryonic cerebellar grafts in Lurcher mice under any conditions, cell suspension engraftment appears a bit more potent than solid grafts of the same origin.…”