Grafting Neural Precursor Cells Promotes Functional Recovery in an SCA1 Mouse Model

Abstract

The B05 transgenic SCA1 mice, expressing human ataxin-1 with an expanded polyglutamine tract in cerebellar Purkinje cells (PCs), recapitulate many pathological and behavioral characteristics of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1), including progressive ataxia and PC loss. We transplanted neural precursor cells (NPCs) derived from the subventricular zone of GFPexpressing adult mice into the cerebellar white matter of SCA1 mice when they showed absent (5 weeks), initial (13 weeks), and significant (24 weeks) PC loss. Only in mice with significant cell loss, grafted NPCs migrated into the cerebellar cortex. These animals showed improved motor skills compared with sham-treated controls. No grafted cell adopted the morphological and immunohistochemical characteristics of PCs, but the cerebellar cortex in NPC-grafted SCA1 mice had a significantly thicker molecular layer and more surviving PCs. Perforated patch-clamp recordings revealed a normalization of the PC basal membrane potential, which was abnormally depolarized in sham-treated animals. No significant increase in levels of several neurotrophic factors was observed, suggesting, along with morphological observation, that the neuroprotective effect of grafted NPCs was mediated by direct contact with the host PCs. We postulate that a similar neuroprotective effect of NPCs may be applicable to other cerebellar degenerative diseases.

Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host

“…This histological improvement was reflected in behavioral improvement (Fig. 4H) (12). In no case was this improvement accompanied by the differentiation of donor neurosphere-derived cells into PNs.…”

“…i) Neurospheres were isolated from the SVZs of 4-8 week-old FVB/N mice transgenic for GFP transcribed from a ubiquitous promoter (12). ii) A stable, well-characterized, clonal population of engraftable mNSCs (C17.2) was used (1,3,5).…”

“…"Gliotic ratio" is the percentage of GFAP+ host cells in OCs divided by % GFAP+ host cells in grafted OCs. SCA1 mouse and nervous models and experimental procedures are detailed in SI Text and elsewhere (5,12). RNA interference (RNAi) for Cx26 and Cx43 (10-100 nM) and RNAi controls; scrambled siRNA, GAPHD siRNA, and nontransfected cells are detailed in SI Text Data are presented as mean ± SEM.…”

Concise Review: Stem Cells for the Treatment of Cerebellar-Related Disorders

“…By contrast, transplantation of these cells to animal models of the transgenic SCA1 gave encouraging results [33]. Grafted SCA1 animals have shown improved motor skills when compared with sham-treated controls [33]. This study, together with studies on other animal models such as multiple sclerosis [34], indicates that transplanted adult NSC could be beneficial for some neurodegenerative disorders.…”

“…By contrast, transplantation of these cells to animal models of the transgenic SCA1 gave encouraging results [33]. Grafted SCA1 animals have shown improved motor skills when compared with sham-treated controls [33].…”