Tendon Tissue Engineering Informed by Lysyl Oxidase Regulation of Embryonic Tendon Mechanical Properties

赖氨酰氧化酶调节胚胎肌腱力学性能的肌腱组织工程

• 批准号: 10471343
• 负责人: Catherine K. Kuo
• 金额: $ 32万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471343
• 关键词: Adult; Affect; American; Benchmarking; Biological; Bioreactors; Chemicals; Chick; Chick Embryo; Chickens; Clinical; Collagen; Cues; Data; Development; Embryo; Embryonic Development; Encapsulated; Engineering; Exhibits; Extracellular Matrix; Frequencies; Functional disorder; Goals; Hydrogels; Impairment; In Vitro; Inferior; Injury; Ligaments; Mammals; Mediating; Medical Care Costs; Mesenchymal Stem Cells; Modeling; Modulus; Movement; Muscle; Musculoskeletal; Natural regeneration; Operative Surgical Procedures; Outcome; Pain; Paralysed; Patients; Pattern; Periodicity; Physical therapy; Protein-Lysine 6-Oxidase; Publishing; Quality of life; Recombinants; Regulation; Risk; Role; System; Tendon Injuries; Tendon structure; Testing; Therapeutic Intervention; Tissue Engineering; Tissues; United States; Work; base; bone; crosslink; density; design; disability; functional restoration; gain of function; healing; improved; inhibitor/antagonist; innovation; loss of function; mechanical load; mechanical properties; musculoskeletal injury; novel; novel strategies; regenerative; stem cell based approach; stem cells; targeted treatment; tendon development; tissue regeneration; treatment strategy

PROJECT SUMMARY Musculoskeletal injuries are a leading cause of disability and medical costs in the United States. Approximately half of these injuries involve tendons and ligaments. The lifelong dysfunction, pain, and increased risk of re- injury due to poor healing have motivated our long-term goal to regenerate new tendon from stem cells to restore function and quality of life. Typical stem cell-based approaches aim to promote quantity of extracellular matrix (ECM) content, with the assumption that ECM quantity correlates with mechanical properties. However, these approaches have yet to achieve functional tendons. This has led us to ask how tendon develops naturally in the embryo to inform a mesenchymal stem cell (MSC)-based tendon regeneration approach. Our studies in the chick embryo recently showed that lysyl oxidase (LOX)-mediated crosslinking correlates strongly with mechanical properties during tendon development, and that inhibition of LOX activity reduces crosslinking and elastic modulus despite continued increases in matrix content. Furthermore, LOX activity appears to be regulated by embryonic kicking (mechanical loading). Based on these exciting data, we hypothesize LOX is a critical regulator of developing tendon mechanical properties, and that developmentally informed manipulation of LOX activity can promote functional tendon regeneration with MSC. The hypothesis will be tested with the following three specific aims: 1) determine LOX expression patterns and role in embryonic tendon mechanical property development; 2) elucidate how mechanical loading regulates LOX during embryonic tendon development; 3) develop approaches to enhance engineered MSC-construct mechanical properties via LOX-mediated crosslinking. The proposed work is innovative because our approach focuses on restoring ECM quality, rather than quantity, of the regenerating tendon matrix, and aims to inform this approach with embryonic development. Our novel strategy combines the chick embryo model with tissue engineering and bioreactor loading systems to investigate LOX and mechanical loading interactions in functional tendon development. Our long-term goal is to design developmentally inspired LOX-targeted therapies utilizing MSC to improve tendon mechanical properties.

项目概要 肌肉骨骼损伤是美国残疾和医疗费用的主要原因。大约 其中一半损伤涉及肌腱和韧带。终生功能障碍、疼痛以及复发风险增加 由于愈合不良造成的损伤促使我们的长期目标是利用干细胞再生新肌腱 恢复功能和生活质量。典型的基于干细胞的方法旨在提高细胞外的数量 基质（ECM）含量，假设 ECM 数量与机械性能相关。然而， 这些方法尚未实现功能性肌腱。这让我们不禁要问，肌腱是如何发育的？ 自然地在胚胎中形成基于间充质干细胞（MSC）的肌腱再生方法。 我们最近对鸡胚的研究表明，赖氨酰氧化酶（LOX）介导的交联 与肌腱发育过程中的机械性能密切相关，并且抑制 LOX 活性 尽管基体含量持续增加，但交联和弹性模量降低。此外，液氧 活动似乎受到胚胎踢动（机械负荷）的调节。基于这些令人兴奋的数据，我们 假设 LOX 是肌腱机械性能发育的关键调节因子，并且在发育过程中 对 LOX 活性的知情控制可以促进 MSC 的功能性肌腱再生。假设 将针对以下三个具体目标进行测试：1）确定 LOX 表达模式和作用 胚胎肌腱机械性能发展； 2) 阐明机械负载如何调节液氧 在胚胎肌腱发育期间； 3) 开发增强工程化 MSC 构建的方法 通过 LOX 介导的交联实现机械性能。 拟议的工作具有创新性，因为我们的方法侧重于恢复 ECM 质量，而不是 再生肌腱基质的数量，旨在为这种方法与胚胎发育提供信息。我们的 新策略将鸡胚模型与组织工程和生物反应器加载系统相结合 研究功能性肌腱发育中液氧和机械负荷的相互作用。我们的长期目标是 利用 MSC 设计受发育启发的 LOX 靶向疗法，以改善肌腱机械性能 特性。

项目成果

Embryo movements regulate tendon mechanical property development.

• DOI: 10.1098/rstb.2017.0325
• 发表时间: 2018-09-24
• 期刊: Philosophical transactions of the Royal Society of London. Series B, Biological sciences
• 作者: Pan XS;Li J;Brown EB;Kuo CK
• 通讯作者: Kuo CK

Roadmap of molecular, compositional, and functional markers during embryonic tendon development.

• DOI: 10.1080/03008207.2018.1511710
• 发表时间: 2018-09
• 期刊: Connective tissue research
• 影响因子: 2.9
• 作者: Nguyen PK;Pan XS;Li J;Kuo CK
• 通讯作者: Kuo CK