Due to the physical demands placed on the knees and shoulders of service members, the incidence of ligamentous injury is high in the Veteran population. These injuries have significant impact on Veterans? quality of life and ability to meet their occupational, recreational, and health goals. There is a need for better treatment options to augment surgical repair or reconstruction for some of these ligament and tendon injuries. In particular, 73% of massive rotator cuff tears fail to heal following surgical repair, and there are limited graft options for anterior cruciate ligament (ACL) reconstruction. In order to address these shortcomings in current surgical options, a biomimetic stem cell-based solution would be ideal. Our approach to this problem is inspired by the body?s own ability to heal after injury. While poorly-vascularized intra-articular ligament injuries such as ACL tears do not heal, well-vascularized extra-articular ligaments such as the medial collateral ligament (MCL) can heal without operative intervention. The exact mechanisms behind this observation are not well-understood. We hypothesize that a major difference between ligament healing and non-healing is access to vascular supply, specifically, vascular-associated mesenchymal stem cells. Pericytes are perivascular stem cell (PSC) population that is associated with blood vessels throughout the body. Studies on tendon remodeling have postulated that pericytes from the tendon sheath are responsible for neo-tendon formation in the event of tendon injury. However, these reports do not provide any empiric evidence to support this hypothesis. It is our goal to provide definitive evidence of this hypothesis by using a lineage tracing mouse model and a model of pericyte ablation to systematically establish the role that pericytes play during ligament healing. We further propose to evaluate the efficacy of using human pericytes to treat injuries to fibrous tissues such as the MCL and for a tissue-engineered ACL graft. Regardless of whether pericytes directly contribute to ligament healing, they remain an attractive clinical option due to ease of isolation and likely trophic effects. Our over-arching goal is to establish a basic science mechanism and proof of concept for PSC-based therapies for ligament and tendon injuries. The overall hypothesis of this highly clinically relevant proposal is that pericytes contribute to extra-articular ligament healing; and that exogenous PSC-based therapies can enhance healing in both intra-articular and extra-articular ligament injuries. If successful, these studies would collectively establish the foundation for new pericyte-based therapies to treat ligament injuries that are unfortunately very common in Veterans. Specifically, these would include both injections to promote the non-operative healing of extra-articular ligament injuries such as MCL sprains, adjunct therapy for surgical treatment of tendon and ligament tears such as rotator cuff injuries, and cell- seeded constructs for the surgical reconstruction of intra-articular ligament injuries such as ACL rupture.
Extra-articular ligaments such as the medial collateral ligament (MCL) often heal without surgery, while intra- articular ligaments such as the anterior cruciate ligament (ACL) do not. We hypothesize that the major difference between the two is access to vascular supply, specifically perivascular stem cells (PSCs). PSCs are an adult stem cell population that are associated with blood vessels throughout the body, and have been shown to differentiate into all mesenchymal lineages, including collagen-producing fibroblasts. We propose to establish that perivascular stem cells are indeed the cells responsible for extra-articular ligament repair by performing lineage tracing of PSCs in a model of MCL injury, and examining healing MCL with partial PSC ablation. Additionally, we plan to characterize the effects of PSCs on MCL healing and a scaffold-based model of ACL reconstruction. Collectively, these studies would establish the foundation for new PSC-based clinical therapies to treat ligament injury.
