Pluripotent Stem Cells Identified in Multiple Murine Tissues

Abstract

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.

A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow

“…To support this notion several studies from our and other laboratories provided direct evidence that BM stem cells are heterogenous and perhaps pluripotent. 25,[26][27][28][29] Accordingly, BM was found to contain endothelial-, 30,31 bone-, [32][33][34] skeletal muscle-, 35 cardiac-, 36,37 hepatic- [38][39][40] and neural-tissue committed stem cells 4,41 and the potential list of versatile stem cells including mesenchymal stem cells (MSC), 42 multipotent adult progenitor cells (MAPC) 43 and as recently reported germ cells 28 is continuously expanding. However, these potential candidate cells had not been characterized well at the singlecell level.…”

Role of bone marrow cell trafficking in replenishing skeletal muscle SP and MP cell populations

“…SP cells were found in many other tissues , but their role, origin, contribution to local tissues and relationship with other SP cells remain largely unknown. One attractive hypothesis is that tissue-specific SP cells derive from a common, circulating stem cell that harbors in other tissues and has the potential to integrate and become a committed progenitor of that tissue (Howell et al, 2003). Because the existence of stem cells within the BM has been well demonstrated and these cells are known to circulate, it seems reasonable to hypothesize that stem cells found in other tissues might also derive from and maintain a relationship with the BM.…”

Very small embryonic-like stem cells in adult tissues—Potential implications for aging

“…Unfortunately the isolation strategy of spore-like stem cells was not clearly described by the authors in the original paper and thus it was not specified how these cells were isolated from adult tissues (Vacanti et al, 2001). In contrast, by employing FACS-based phenotypic analysis of single cell suspensions prepared from murine brain, blood, and intestinal epithelium, Howell et al revealed the presence of very small CD45 − Sca-1 + c-kit − cells in varying degrees that may represent universal pluripotent stem cells residing at different levels in multiple murine tissues (Howell et al, 2003). Very small stem cells with neuroblast activity were also recently found in the subventricular zone of the murine brain (Scheffler et al, 2005).…”