Somatic stem cells (adult stem cells) are essential for homeostatic maintenance of various tissues. In addition to normal homeostasis, they are also involved in tissue regeneration in case of injury. Interestingly, adult stem cell function declines with age and this phenomenon limits tissue regeneration in aged tissues. To understand the molecular basis of the functional decline in aged stem cells, we will investigate how canonical Wnt signaling is involved to regulate cell fate decisions in tissue homeostasis and repair. We are using muscle stem cells (MuSCs) as a model stem cell system, our preliminary data suggests that an adequate intrinsic level of ß-Catenin, the main effector of canonical Wnt signaling, is required for MuSC function during muscle regeneration. We thus began to examine how Wnt/ß-Catenin signaling functions as a pleiotropic pathway to regulate both myogenic differentiation and cell fate decisions. Accumulated evidence has suggested that rejuvenation of aged stem cell populations can be performed and that such mechanism can be controlled in an epigenetic fashion. However, the extent to how this cellular reprogramming event works is unclear. Wnt signals are a key sources of cues that direct myogenic lineage progression and it has also been implicated in promoting MuSC to adapt an alternative fate in aged muscle, rendering MuSC dysfunctional and resulting in an impairment of muscle regeneration in aged animals. We thus propose to understand the molecular and epigenetic regulation of canonical Wnt signaling in MuSCs during organismal ageing. Our project aims to decipher the role(s) of canonical Wnt/ß-Catenin in MuSCs cell fate decisions during ageing. Using Cre/Lox genetic approaches, we will first assess and compare the implication of ß-Catenin in young and old MuSCs function. As aged MuSCs can be rejuvenated and thus appear not genetically altered, we will then focus on understanding the age-related changes in epigenetic determinants in MuSCs, and whether canonical Wnt signaling is differentially controlling asymmetric divisions of young and old MuSCs. This project is lead by an interdisciplinary consortium comprises of researchers in France and Hong Kong studying molecular regulation of stem cell function. Members of this consortium have complementary expertise in the area of stem cell biology, computational biology and genetics. It is expected our study will contribute to the understanding of MuSC fate during normal ageing. We strongly believe this proposal will provide new insights as to the molecular mechanisms that regulate stem cell ageing. The result of this proposal will lead to the identification of new selective targets for the development of therapy for stem cell rejuvenation.