It is estimated that 2% of the population sustain fractures annually, which in Europe corresponds to approximately 15 millions fractures and in France 1 million fractures. Although bone exhibits strong regenerative properties, delayed unions and non-unions still occur at a frequency of 5 to 10% in all skeletal injuries leading to patient disability and high societal cost. Bone repair is dependent on the proliferation and differentiation of skeletal stem/progenitor cells. The exact origins and functions of these cells are not clearly understood. Our long-term goal is to elucidate the mechanisms of skeletal stem cell recruitment during bone regeneration in order to support the development of new cell based therapies for bone repair. In the past 10 years, I have established several mouse models of bone repair combined with cell lineage analyses in vivo. These approaches based on genetic labeling and bone transplantation allow tracking the fate of tissues and cells during bone development and repair. In Aim 1, we will track mesenchymal lineages in development and repair, in order to understand how adult skeletal stem cell populations are established in bone. Aim 2 will directly compare the contribution of local versus systemic sources of skeletal stem cells and the effects of environmental factors such as extreme trauma on their relative contributions. Aim 3 will functionally assess the molecular regulation of skeletal cell fate decisions within bone marrow and periosteum (which lines the outer surface of bone) during fracture healing.Following my postdoctoral training, I have worked for 5 years at University of California San Francisco to develop an independent research program supported by extramural funding. This project will use my expertise accumulated over the years and research support is crucial to pursue my goals and establish a new research team at INSERM U781, Necker Hospital for Sick Children in Paris starting in the spring of 2010.