The processes governing stem cell generation and subsequent stem cell renewal and differentiation are poorly understood. With the exception of lower vertebrates, the existence of an identifiable and functional compartment of postnatal pluripotent stem cells which participate in multiple lineages has been difficult to identify in higher vertebrates. What limited regenerative potential mammals display declines rapidly with age and is compromised further in many disease states. We have been studying the role of PW1 which is a p53 induced gene involved in cell death and which also mediates the TNFalpha/NFkB signaling pathway. During development, PW1 is expressed during early mesodermal specification and maintained at high levels in stem cells residing in post-natal skeletal muscle. Taken together, these observations lead to the proposal that PW1 mediates stem cell behavior through p53 and cytokine/NF_B signaling pathways in these cells. We note that there is little information available regarding postnatal pluripotent stem cells due in part to their inability to undergo significant expansion in vitro and a high sensitivity to their host environment including inflammatory cytokines (i.e. TNFalpha). Related to these studies is the fact that skeletal muscle is highly sensitive to chronically elevated levels of inflammatory cytokines and undergoes wasting (cachexia) in response to TNFalpha which accounts for significant patient morbidity in cancer and chronic infection. A similar process of muscle atrophy accompanies aging and is also seen in mice with increased p53 activity. Data obtained in our laboratory has revealed an unexpected mechanistic link between the TNFalpha and p53 pathways that is unique to skeletal muscle cells which is mediated through PW1 activity. We propose these signaling pathways are active in the stem cell population and in a manner related to the ability of p53 to dictate cell fate outcomes, the p53-PW1 pathway may modulate stem cell number and competence in postnatal muscle tissue. In this proposal, we will use in vitro models (cell culture) and in vivo (mouse) models to explore the roles of PW1, p53 and cytokine signaling pathways in skeletal muscle stress responses and stem cell regulation. The relationship between the muscle stress/cachectic responses, aging and stem cell regulation is poorly understood although stem cells are required to maintain muscle growth and are thought to diminish in number and/or potential during postnatal life. We will address the central hypothesis that p53/PW1 pathways converge to regulate stem cell allocation and fate in the skeletal muscle lineage.
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