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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 and embryonic stem cell–derived neural precursors—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 toward acquisition of a 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. STEM CELLS 2009;27:1625–1634

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