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: 10552614
• 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/10552614
• 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; Infiltration; 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; Reconstructive Surgical Procedures; Recreation; Reporting; Role; Shoulder; Site; Source; Sprain; Tamoxifen; Techniques; Tendon Injuries; Tendon structure; Therapeutic; Tissue Engineering; Tissues; Vascular blood supply; Vascularization; Veterans; Wild Type Mouse; adult stem cell; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; clinically relevant; collateral ligament; directed differentiation; 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.

由于对服务人员的膝盖和肩膀的身体要求， 韧带损伤在退伍军人中的发生率很高。这些伤害对退伍军人的质量有重大影响 生活和能力，以满足他们的职业，娱乐和健康目标。需要更好的治疗 选择增加手术修复或重建这些韧带和肌腱损伤的一些。在 特别是，73%的巨大肩袖撕裂在手术修复后无法愈合， 前交叉韧带（ACL）重建的选择。为了解决当前的这些缺点， 手术选择，仿生干细胞为基础的解决方案将是理想的。 我们解决这个问题的方法是受到身体自身受伤后愈合能力的启发。虽然血管化不良 关节内韧带损伤如ACL撕裂不能愈合，血管化良好的关节外韧带如 因为内侧副韧带（MCL）可以在不进行手术干预的情况下愈合。背后的确切机制 这一观察结果还没有得到很好的理解。我们假设韧带愈合和 而不愈合是血管供应，特别是血管相关的间充质干细胞。 周细胞是血管周围干细胞（PSC）群体，其在整个组织中与血管相关。 身体关于肌腱重塑的研究已经假设来自腱鞘的周细胞负责 在肌腱损伤的情况下形成新肌腱。然而，这些报告没有提供任何经验性的 支持这一假设的证据。我们的目标是通过使用一个 谱系追踪小鼠模型和周细胞消融模型，以系统地建立周细胞 在韧带愈合期间玩耍。我们进一步建议评估使用人周细胞治疗 例如MCL和组织工程ACL移植物的纤维组织损伤。无论 尽管周细胞直接有助于韧带愈合，但由于其易于治疗，它们仍然是有吸引力的临床选择。 隔离和可能的营养效应。我们的总体目标是建立一个基本的科学机制和证据 基于PSC的韧带和肌腱损伤治疗的概念。这一高度的整体假设 临床相关的建议是，周细胞有助于关节外韧带愈合;外源性 基于PSC的治疗可以促进关节内和关节外韧带损伤的愈合。 如果成功，这些研究将共同为基于周细胞的新疗法奠定基础， 不幸的是，韧带损伤在退伍军人中很常见。具体而言，这将包括 注射以促进关节外韧带损伤（如MCL扭伤）的非手术愈合， 用于肌腱和韧带撕裂（如旋转套损伤）的手术治疗的辅助疗法，以及细胞- 用于关节内韧带损伤（如ACL断裂）的手术重建的植入结构。

项目成果

Rehabilitation Principles to Consider for Anterior Cruciate Ligament Repair.

前十字韧带修复需要考虑的康复原则。

• DOI: 10.1177/19417381211032949
• 发表时间: 2022
• 期刊: Sports health
• 影响因子: 3.3
• 作者: Wu,Jocelyn;Kator,JamieL;Zarro,Michael;Leong,NatalieL
• 通讯作者: Leong,NatalieL

Outcomes of Partial Meniscectomy in Obese Patients: A Systematic Review and Meta-Analysis.

肥胖患者部分半月板切除术的结果：系统评价和荟萃分析。

• DOI: 10.1177/1947603520923025
• 发表时间: 2021
• 期刊: Cartilage
• 影响因子: 2.8
• 作者: Zhang,Tina;Jauregui,JulioJ;Foster,Michael;Packer,JonathanD;Meredith,SeanJ;Leong,NatalieL;Henn3rd,RFrank
• 通讯作者: Henn3rd,RFrank

Impact of Postoperative Opioid Use on 2-Year Patient-Reported Outcomes in Knee Surgery Patients.

膝关节手术患者术后使用阿片类药物对 2 年患者报告结果的影响。

• DOI: 10.1055/s-0040-1722326
• 发表时间: 2022
• 期刊: The journal of knee surgery
• 作者: Song,Xuyang;Sajak,PatrickMJ;Aneizi,Ali;Alqazzaz,Aymen;Burt,CameranI;Ventimiglia,DominicJ;Meredith,SeanJ;Leong,NatalieL;Packer,JonathanD;Henn3rd,RFrank
• 通讯作者: Henn3rd,RFrank

Preoperative Factors Associated with Press Ganey Patient Satisfaction Scores after Anterior Cruciate Ligament Reconstruction.

与前十字韧带重建后 Press Ganey 患者满意度评分相关的术前因素。

• DOI: 10.1055/s-0041-1741394
• 发表时间: 2023
• 期刊: The journal of knee surgery
• 作者: Perraut,GregoryT;Zhang,Tina;Weir,TristanB;Schneider,MatheusB;Aneizi,Ali;Leong,NatalieL;Packer,JonathanD;Meredith,SeanJ;Henn3rd,RFrank
• 通讯作者: Henn3rd,RFrank

Biomechanical Comparison of Four- versus Six-Strand Transosseous Suture Repair for Patellar Tendon Rupture.

四股与六股经骨缝合线修复髌腱断裂的生物力学比较。

• DOI: 10.1055/s-0043-1766094
• 发表时间: 2024
• 期刊: The journal of knee surgery
• 作者: Zhang,Tina;Wahl,Alexander;Schneider,Matheus;Xu,Dali;Hahn,Alexander;Meredith,SeanJ;Packer,JonathanD;Leong,NatalieL;Zhang,Li-Qun;Henn3rd,RFrank;Jauregui,JulioJ
• 通讯作者: Jauregui,JulioJ