Transplantation of Embryonic and Adult Neural Stem Cells in the Granuloprival Cerebellum of the Weaver Mutant Mouse

Abstract

Numerous studies have explored the potential of different stem and progenitor cells to replace at-risk neuronal populations in a variety of neurodegenerative disease models. This study presents data from a side by side approach of engrafting two different stem/progenitor cell populations within the postnatal cerebellum of the weaver neurological mutant mouse: cerebellar-derived multipotent astrocytic stem cells (MASCs) and embryonic stem cell-derived neural precursor (ESNPs), for comparative analysis. We show here that both donor populations survive, migrate, and appear to initiate differentiation into neurons within the granuloprival host environment. Neither of these disparate stem/progenitor cell populations adopted significant region-specific identities despite earlier studies that suggested the potential of these cells to respond to in vivo cues when placed in a permissive/instructive milieu. However, data presented here suggest that molecular and cellular deficits present within weaver homozygous or heterozygous brains may promote a slightly more positive donor cell response towards acquisition of neuronal phenotype. Hence it is likely that a fine balance exists between a compromised host environment that is amenable to cell replacement and that of a degenerating cellular milieu where it is perhaps too deleterious to support extensive neuronal differentiation and functional cellular integration. These findings join a growing list of studies that show successful cell replacement depends largely on the interplay between the potentiality of the donor cells and the specific pathological conditions of the recipient environment, and that emergent therapies for neurological disorders involving the use of neural stem cells still require refinement.

Cellular fusion for gene delivery to SCA1 affected Purkinje neurons

“…While we would have liked to see the present combined stem cell fusion-gene therapy approach have a more profound therapeutic effect, an accumulating body of evidence, including studies of other cerebellar mutant mouse models (e.g. Weaver mouse which exhibits profound granule cell loss, versus the Purkinje cell loss studied here) suggests that cues from at-risk neurons may not be enough to support stem cell repair or replacement (Chen et al, 2009). Possibly a result of too much cellular damage and an overall toxic environment, it is clear that complementary methods will need to be developed to enhance stem cell engraftment and repair, either through fusogenic stem cell rescue or widespread cellular replacement.…”

Stem Cells in Tooth Tissue Regeneration—Challenges and Limitations

“…As these interactions at molecular level are elucidated in more detail, the notion of obtaining specific differentiated cell types from stem cells to be used for ex vivo tissue generation with the purpose of implanting it give way to a more nuanced approach of utilizing stem cells in in situ configuration where they can influence the multicellular milieu to achieve the regenerative outcome sufficient for normal function [67,68]. The realization that implanted stem cells of adult or embryonic origin integrates into the host neural tissues and triggers the regenerative response with improved function as a result of trophic action and stimulation of the resident populations, but not conversion into neural cells underscores this shift of paradigm [69,70]. Such an approach could suite well to dental tissue regeneration aimed at periodontal or endodontic structures.…”

Experimental neurotransplantation treatment for hereditary cerebellar ataxias

“…In Weaver mutant mice, grafted cerebellar-derived multipotent astrocytic stem cells and embryonic stem cell-derived neural precursors were not capable of adopting region-specific cell identities, but the milieu of the granuloprival host cerebellum provided signals slightly supporting neuronal differentiation of donor cells [ 67 ].…”