Role of Perivascular Stem Cells in Ligament Healing and Regeneration

血管周围干细胞在韧带愈合和再生中的作用

• 批准号: 10355432
• 负责人: Natalie L Leong
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355432
• 关键词: Ablation; Address; Anterior Cruciate Ligament; Articular ligaments; Basic Science; Biomimetics; Blood Vessels; Cells; Clinical; Collagen; Event; Fibroblasts; Foundations; Genetic; Goals; Histologic; Human; In Vitro; Incidence; Injection of therapeutic agent; Injections; Injury; Intervention; Knee; Label; Ligaments; Medial; Mediating; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Mus; Natural regeneration; Occupational; Operative Surgical Procedures; Pericytes; Platelet-Derived Growth Factor beta Receptor; Play; Process; Quality of life; Rattus; Reporting; Role; Shoulder; Site; Source; Sprain; Tamoxifen; Techniques; Tendon Injuries; Tendon structure; Therapeutic; Tissue Engineering; Tissues; Vascular blood supply; Veterans; Wild Type Mouse; adult stem cell; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; base; clinically relevant; collateral ligament; efficacy evaluation; experimental study; healing; health goals; improved; in vivo; ligament injury; military veteran; mouse model; polycaprolactone; reconstruction; repaired; rotator cuff injury; rotator cuff tear; scaffold; service member; stem cell population; stem cell therapy; stem cells

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.

由于对服役人员的膝盖和肩膀的体力要求，发病率