Understanding and Enhancing the Regenerative Capacity of Skeletal Muscle to Trauma by Targeting Muscle-Nerve Synergy
Abstract
Severe muscle injuries stemming from lower-limb extremity trauma are an enormous medical problem ($400 billion/year ascribed to trauma in the continental United States) and significantly impacts Department of Defense readiness and performance (>24 million limited duty days in 2005). The debilitating consequences of severe muscle injuries from lower-limb extremity trauma have been shown to result in pronounced disabilities ranging from declines in limb function to development of osteoarthritic pathology and delayed or elected limb amputation. Recovery after lower-limb muscle injuries requires replacement of new muscle fibers, which are created from resident stem cells called satellite cells (MuSCs). To restore tissue function, new muscle fibers require attachment of nerve cells through the neuro-muscular junction (NMJ), which couple excitation signals from the brain into the muscle contractile machinery. To date, the intricate relationship between satellite cells and the NMJ is not fully understood, and as such, how neural control influences muscle regeneration and response to trauma remains an open question. The first aim of this project is to understand how the regenerative capacity of MuSCs is altered when the NMJ is disrupted. We have developed an animal model that permits study of NMJ disruption and MuSC response and will use this model to administer severe trauma followed by study of MuSCs using integrative genomic assays during the recovery process. These studies will provide the first mechanistic insights into the intrinsic molecular mechanisms and signaling pathways that neural control exerts on muscle regeneration after trauma -- a currently undefined question. This information can be used by medical personnel to understand recovery, track treatment efficacy, and develop personalized therapies for Service members. The repair and regeneration of severely damaged soft tissues such as skeletal muscle remains a substantial clinical challenge and relatively few treatments exist. An ideal strategy would be to transplant the body’s own MuSCs to regenerate the tissue, but this approach has been inherently limited by challenges such as cell death after transplantation and low integration with host tissue. We have recently observed that manipulations through the NMJ can enhance MuSC engraftment and improve their regenerative potential effectively surmounting these challenges. The second aim of this project will explore utilization of this synergy and quantify parameters of how the NMJ niche enhances MuSC transplantation efficacy after traumatic injury. Successful completion of this aim will represent a leap-ahead advance in cell therapies and significantly enhance the promise of regenerative medicine. The outcomes and knowledge gained from this project will be formulated into preclinical niche-directed therapies to promote muscle regenerative potential and long-term function of patients with traumatic injury. The ability to regenerate tissues and organs with regenerative medicine strategies possesses enormous potential to save or improve the lives of wounded Warriors. Knowledge of the factors that regulate and enhance in vivo MuSC activity remain poorly understood. Our preliminary experiments have shown MuSCs express receptors for signals secreted by neuronal cells and respond to these paracrine signals by differentiation and hypertrophy. In the third aim of this proposal, we will evaluate how co-delivery of MuSCs and neurotrophic factors within a biofunctional hydrogel augments functional recovery after administration of muscle trauma. This platform can potentially be used to deliver MuSCs with other drugs and factors that target other components of regeneration. Successful completion of this study can galvanize precision care of musculoskeletal trauma to reduce the medical cost and loss associated with recovery.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010336
Entities
People
- Carlos A Aguilar
Organizations
- United States Army
- University of Michigan