Pluripotential stem cells (PSCs) have been recently described in many tissues including skeletal muscle, brain, and bone marrow. However, the true nature of these cells is still unclear, and their precise definition has yet to be determined. We hypothesized that a common, rare population of PSCs with a broad tissue differentiation potential can be identified in multiple murine tissues and that these cells are capable of transdifferentiation into cells of different primordial germ layer origins in response to diverse microenvironmental cues. To examine this hypothesis, we isolated phenotypically defined cells from murine skeletal muscle and cultured these cells under different conditions tailored to promote differentiation into several cell types including myocytes. We report here that in conditions permissive for hematopoietic differentiation, muscle-derived CD45(-)Sca-1(+)c-kit(-) cells differentiated into cells expressing hematopoietic-specific mRNA; while in conditions promoting myogenic, neuronal, and adipocytic differentiation, cells morphologically typical of these cell types expressing tissue-specific markers were identified 9-14 days in culture. When CD45(-)Sca-1(+)c-kit(-) cells from muscle or bone marrow were transplanted intracerebellarly into Purkinje cell degenerative (pcd) mice, the behavior of these mice improved 28 days after transplantation relative to mice injected with vehicle alone, suggesting that these cells contributed to the appearance of functional neuronal cells that may have improved the ataxic condition characteristic of these mice. Phenotypic analysis of single cell suspensions prepared from brain, blood, and intestinal epithelium revealed the presence of CD45(-)Sca-1(+)c-kit(-) cells in varying degrees. These studies suggest that a phenotypically common, multipotent cell can be identified in different tissues and that this cell may represent a universal pluripotent stem cell residing at different levels in multiple murine tissues.