Pluripotential stem cells (PSC0 with transdifferentiation capacity have a remarkable potential utility in the treatment of a large number of malignant and non-malignant diseases. Although the fate of stem cells has been considered irreversible and predestined to remain confined to within one tissue type, the plasticity and adaptability of stem cells to differentiate into multiple lineages in response to diverse microenvironmental cues has been recently documented. The degree of stem cell plasticity displayed by embryonic and adult PSC and the relative ease with which stem cells have been instructed to differentiate into tissues of different primordial germ layer origin promise new and exciting avenues for cellular therapy. Yet at present, we remain unaware of the true identity of PSC that have been described and ignorant as to whether a universal stem cell can be identified in different fetal and adult tissues. To better understand and evaluate the plasticity of PSC and to investigate how their differentiation programs can be manipulated, 3 specific aims will be examined. First, we hypothesize that a common rare population of PSC with multiple tissue differentiation potential can be identified in skeletal muscle, bone marrow and brain tissue and that all are capable of transdifferentiation into functional myogenic, hematopoietic and neuronal cells. Second, we will investigate if these stem cells are capable, through self-renewal division in one site and migration to another, of clonal pluripotential differentiation into specialized cells of different tissue types. Third, we will examine whether the fate of this common stem cell can be modulated in vitro and test if, in response to different exogenous stimuli, differentiation into one tissue type can be favored over other differentiation pathways. Studies proposed in this application are responsive to 4 of the primary research needs identified in this Request for Applications. Only be examining parameters that influence the plasticity of these cells such as pluripotential differentiation, clonality, homing and in vitro manipulation of their fate, would it be possible to forward the field of PSC research towards clinical relevance and therapeutic applicability.
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