Deciphering multi-scale differentiation and patterning cues driving whole craniofacial joint regeneration

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PROJECT SUMMARY Joint injuries and diseases are the leading causes of disability worldwide. Synovial joints are composed of complex and structurally integrated tissues, including specialized lubricating articular cartilage and connective tissues like ligaments that stabilize joint movement. In mammals, joint tissues have a poor healing capacity. Even after reconstructive surgery, ligaments fail to reestablish the biomechanical properties of uninjured joints, leaving patients at high risk for re-injury or degenerative joint disease. This limited healing capacity results from a failure of differentiation involving the development of scar tissue in place of mature ligamentocyte and chondrocyte lineages. Currently, we have a limited understanding of the underlying molecular cues that drive lineage specification of the most functionally critical joint cell types, particularly articular cartilage and ligaments. In order to devise improved strategies for regenerative medicine therapeutics for joint tissues, this project will leverage a unique whole joint regeneration model in the highly regenerative zebrafish. While joint injuries fail to heal in mammalian models, we find that endogenous skeletal progenitor cells robustly regenerate synovial joint tissues after a catastrophic injury in zebrafish. The new joint integrates with surrounding tissues to restore biomechanical function. Critically, this high regenerative capacity includes the differentiation of new lubricating articular cartilage and fully integrated new joint-supporting ligaments. Here, through combined genetic and spatial analyses, we will identify and functionally dissect the underlying molecular regulation of progenitors and characterize their physical interactions with their respective regenerative niches required to regenerate complex 3D joint tissues. This high-risk/high-reward proposal will have wide-ranging impacts on our understanding of joint regeneration via repair from endogenous cell sources and inform improved tissue engineering approaches to whole joint replacement in joint disease.