Deciphering the periosteal skeletal stem cell niche to optimize bone regeneration strategies.

Healing of large bone defects remains a medical challenge and scientists intensively search to find alternatives for bone autografts, which possess high repair potency but also induce major side effects. A promising strategy is bone tissue engineering consisting of a combination of stem cells, biomaterials and signaling molecules. Bone repair critically depends on intact periosteum and we have shown that it contains numerous skeletal stem cells (SSCs), although their exact identity is still elusive. SSCs rapidly lose their stemness when they are cultured ex vivo, likely because they become devoid of the environmental cues present in the in vivo niche. Insight in the properties of the periosteal niche is thus required, but given the multitude of factors regulating stem cell function, this approach would be extremely complex. We therefore postulate that these nichespecific signals in the early fracture callus are translated in metabolic adaptations that define the balance between quiescence and activation of SSCs. To this end, we will determine the exact identity and location of SSCs in the mouse periosteum and track their fate and contribution during bone healing. Next, we will link the metabolic profile of SSCs with their state of quiescence or activation. Together these data will be used to develop a computer model to identify key signaling and metabolic pathways regulating SSC behavior. This insight will allow us to create an ex vivo niche that promotes SSC maintenance and results in improved in vivo bone formation;