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（由申请人提供）：肌腱撕裂是常见的肌肉骨骼损伤，其愈合后不会恢复功能结构。愈合肌腱无法恢复功能结构会导致损伤进展以及手术修复后高发生率的撕裂。无疤痕肌腱愈合以及恢复的天然组织特性可以改善手术结果或完全消除手术修复的需要，但通常不会在产后哺乳动物中观察到。成年墨菲罗斯大型 (MRL/MpJ) 小鼠表现出再生能力的发现使该小鼠品系成为研究成年再生愈合机制的令人兴奋的模型。对 MRL/MpJ 小鼠再生机制的研究产生了涉及全身和局部组织水平的假设，但尚无确凿的数据。拟议的研究探讨了 MRL/MpJ 小鼠的全身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 肌腱的无疤痕愈合是由独特的临时细胞外基质 (ECM) 介导的，该基质促进基质生成细胞的排列和增殖的改善，但最终不会因基质金属蛋白酶 9 (MMP9) 的分解代谢活性增加而导致过度的基质沉积。除了我们发表的数据表明 MRL/MpJ 小鼠在中质击打损伤中表现出更好的愈合能力之外，支持这一新假设的其他证据包括：(1) 数据表明，再生 MRL/MpJ 小鼠中的临时 ECM 在结构和成分上与愈合 B6 肌腱时的临时 ECM 不同；(2) 数据表明，在愈合的早期阶段，MRL/MpJ 在这种明显不同且排列更好的临时 ECM 的背景下，肌腱表现出细胞增殖增加和排列改善；(3) 相关数据显示 MMP9 表达增加，临时 ECM 被排列更好的长期 ECM 取代。我们建议询问有助于 MRL/MpJ 独特临时 ECM 合成的全身和局部因素（目标 2），并阐明该临时 ECM 在调节细胞反应中的作用（目标 1）。我们还将探索源自 MRL/MpJ 愈合肌腱的临时 ECM 的治疗潜力，以促进疤痕介导的 B6 小鼠的无疤痕肌腱愈合（目标 3）。利用新颖的显微外科技术和近交小鼠品系来解开全身环境和肌腱对无疤痕肌腱愈合的影响。肌腱器官培养也可用于确定再生 MRL/MpJ 小鼠的临时 ECM 在调节细胞活性以实现无疤肌腱愈合中的作用。这些研究通过分离先天肌腱和全身环境对无疤肌腱愈合的贡献，为治疗干预措施的发展奠定了基础。 MRL/MpJ 的临时 ECM 作为一种治疗干预措施的潜在效用，利用生物和结构队列实现无疤肌腱愈合，可能对肌腱组织工程领域产生巨大影响。