Nell1-mediated Regeneration of Skeletal Muscle in Wound Healing and Muscle Dystrophies

The Culiat Lab at ORNL discovered the functions of the potent and novel Nell1 signaling protein in the formation of major components of the mammalian musculoskeletal (bone, cartilage and muscle) and cardiovascular system (heart muscle and vasculature). Nell1 triggers pathways that promote the formation of the complex blood vessel and capillary networks into developing tissues and the maturation of specific cell types to properly secrete components of the extracellular matrix (ECM). The natural healing of injured muscle occurs in three stages: 1) Destruction - characterized by haematoma, necrosis, degeneration and inflammation; 2) Repair - wherein muscle satellite cells are activated to proliferate, differentiate and fuse into new muscle fibers. This stage requires capillary ingrowth and rebuilding of the ECM architecture secreted by fibroblasts ; 3) Remodeling – wherein newly regenerated muscle matures and contracts with the reorganization of the scar tissue (Menetrey et al. J Bone Joint Surg, 2000; Charge and Rudnicki, Physiol Rev, 2004). Data from the contractor, along with published literature on the molecular mechanisms of muscle regeneration strongly suggest that genes/proteins playing critical roles in stages 2 and 3 are under the control of Nell1 (eg. Osf2/periostin, tenascins, collagens and proteoglycans of the ECM etc.), thus suggesting the therapeutic potential of Nell1 in facilitating muscle regeneration and wound healing.