THE ROLE OF THE EXTRACELLULAR MATRIX IN SCARLESS TENDON HEALING

细胞外基质在无疤痕肌腱愈合中的作用

• 批准号: 9112871
• 负责人: NELLY Andarawis-Puri
• 金额: $ 34.14万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112871
• 关键词: Adult; Apoptosis; Autologous Transplantation; Back; Biological; Cell Proliferation; Cells; Characteristics; Cicatrix; Data; Deposition; Development; Ear; Elastin; Environment; Exhibits; Extracellular Matrix; Failure; Fatigue; Fibronectins; Foundations; Gelatinase B; Harvest; Hyaluronan; Inbred Strains Mice; Incidence; Inflammation; Injury; Investigation; Knowledge; Laceration; Lead; Mammals; Mechanics; Mediating; Modeling; Mouse Strains; Mus; Natural regeneration; Operative Surgical Procedures; Organ Culture Techniques; Outcome; Pathway interactions; Phase; Play; Property; Proteoglycan; Publishing; Role; Rupture; SCID Mice; Site; Structure; Techniques; Tendon Injuries; Tendon structure; Therapeutic; Therapeutic Intervention; Time; Tissue Engineering; Tissues; Transplantation; blastema; functional restoration; healing; improved; in vivo; inflammatory milieu; injured; migration; musculoskeletal injury; novel; postnatal; public health relevance; regenerative; repaired; response; therapeutic development; therapy development; tissue regeneration

 DESCRIPTION (provided by applicant): Tendon tears are common musculoskeletal injuries that heal without restoration of the functional structure. Failure of healing tendons to restore th functional structure leads to progression of injury and high incidence of retear after surgical repair. Scarless tendon healing, with restored native tissue properties, could improve surgical outcome or eliminate the need for surgical repair altogether, but is not typically observed in postnatal mammals. The discovery that adult Murphy Roths Large (MRL/MpJ) mice exhibit a regenerative capacity has distinguished this mouse strain as an exciting model to investigate mechanisms that underlie adult regenerative healing. Investigation into the regenerative mechanisms of MRL/MpJ mice has generated hypotheses that implicate both, the systemic and local tissue level, but no conclusive data exists. The proposed studies interrogate the contribution of the systemic environment of the MRL/MpJ mouse and the local environment of its tendon to scarless tendon healing. Our hypothesis is that scarless healing in MRL/MpJ tendons is mediated by a unique provisional extracellular matrix (ECM) that promotes improved alignment and proliferation of matrix producing cells but does not ultimately lead to excessive matrix deposition due to increased catabolic activity of Matrix Metalloproteinase 9 (MMP9). In addition to our published data that show that MRL/MpJ mice exhibit improved healing in midsubstance punch injuries, additional evidence that supports this novel hypothesis includes: (1) data that show that the provisional ECM in regenerative MRL/MpJ mice differs in structure and composition than the provisional ECM in healing B6 tendons; (2) data that show that during the early phases of healing, MRL/MpJ tendons exhibit increased cell proliferation and improved alignment in the context of this distinctly different and better aligned provisional ECM; and (3) correlated data that show increased expression of MMP9 and a provisional ECM that is replaced by a better aligned long term ECM. We propose to interrogate the systemic and local factors that contribute to synthesis of MRL/MpJ's unique provisional ECM (Aim 2) and elucidate the role of this provisional ECM in modulating the cellular response (Aim 1). We will also explore the therapeutic potential of the provisional ECM derived from MRL/MpJ healing tendons to promote scarless tendon healing in scarmediated B6 mice (Aim 3). Novel microsurgical techniques and inbred mouse strains are utilized to uncouple the contribution of the systemic environment and the tendon to scarless tendon healing. Tendon organ culture is also employed to determine the role of the provisional ECM from regenerative MRL/MpJ mice in modulating the cellular activity that leads to scarless tendon healing. These studies set the foundation for development of therapeutic interventions by isolating the contributions of the innate tendon and the systemic environment to scarless tendon healing. The potential utility of MRL/MpJ's provisional ECM as a therapeutic intervention that harnesses the biological and structural queues that lead to scarless tendon healing could be highly impactful for the field of tendon tissue engineering.

 描述（由适用提供）：肌腱眼泪是常见的肌肉骨骼损伤，而无需恢复功能结构。恢复肌腱恢复TH功能结构的失败会导致手术修复后的损伤进展和高率入口。具有恢复的天然组织特性的无疤痕肌腱愈合可以改善手术结局或完全消除对手术修复的需求，但通常在产后哺乳动物中观察到。成年墨菲·罗斯（Murphy Roth）大型（MRL/MPJ）小鼠暴露了再生能力的发现将这种小鼠菌株区分为一种令人兴奋的模型，以研究基于成人再生愈合的机制。对MRL/MPJ小鼠的再生机制的调查已经产生了涉及全身组织和局部组织水平的假设，但不存在结论性数据。拟议的研究询问了MRL/MPJ小鼠的系统环境及其肌腱的局部环境对无疤痕肌腱愈合的贡献。我们的假设是，MRL/MPJ肌腱中无疤的愈合是由独特的临时细胞外基质（ECM）介导的，该基质（ECM）促进了基质生产细胞的对齐和增殖的改善和增殖，但最终并没有导致Matrix Metallopoteinase 9（MMP9）的分类代谢性增加而导致过量的基质沉积。除了我们发表的数据表明，MRL/MPJ小鼠在Midsubstance Punch损伤中暴露了改善的愈合外，其他支持此新假设的证据还包括：（1）数据表明，与临时ECM相比，在结构和成分中的临时ECM在结构和成分中的临时ECM在愈合的B6型B6型中的差异； （2）数据表明，在愈合的早期阶段，MRL/MPJ肌腱展示了我们的细胞增殖，并改善了WE中的一致性，我们还将探索有助于合成MRL/MPJ独特的临时ECM（AIM 2）的系统和局部因素（AIM 2），并阐明了这种临时ECM在调制细胞响应中的作用。我们还将探索源自MRL/MPJ愈合肌腱衍生的临时ECM的治疗潜力，以促进破碎的B6小鼠中无疤痕肌腱愈合（AIM 3）。新型的微外科技术和近交小鼠菌株用于脱离系统环境的贡献以及肌腱对无疤痕肌腱愈合的贡献。还采用了肌腱器官培养，以确定再生MRL/MPJ小鼠的临时ECM在调节导致无疤痕肌腱愈合的细胞活性中的作用。这些研究通过隔离先天肌腱和系统环境对无疤痕肌腱愈合的贡献来为发展理论干预的发展提供了基础。 MRL/MPJ的临时ECM作为一种治疗性干预措施的潜在效用，该干预措施利用导致无疤痕肌腱愈合的生物学和结构排队对肌腱组织工程领域的影响很大。