Identification of Muscle-Derived Soluble and Mechanical Cues to Direct Differenti

识别肌肉衍生的可溶性和机械线索以直接区分

• 批准号: 8459446
• 负责人: Catherine K. Kuo
• 金额: $ 6.94万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459446
• 关键词: Adult; Cell Differentiation process; Cell secretion; Coculture Techniques; Complex; Cues; Development; Developmental Biology; Dose; Embryo; Embryonic Development; Engineering; Environment; Failure; Figs - dietary; Future; Goals; Growth Factor; Healed; In Vitro; Individual; Knock-out; Knowledge; Lead; Ligaments; Maintenance; Mechanical Stimulation; Mechanics; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Motivation; Mus; Muscle; Muscle Cells; Muscle Fibers; Myoblasts; Natural regeneration; Operative Surgical Procedures; Outcome; Outcome Study; Outcomes Research; Patients; Play; Process; Production; Public Health; Role; Rupture; Schedule; Signal Transduction; Site; Staging; Stem cells; System; Tendon structure; Time; Tissue Engineering; Tissues; Transforming Growth Factors; Translating; Work; base; growth differentiation factor 5; healing; in vivo; injured; innovation; novel; progenitor; reconstruction; repaired; scaffold; stem; tissue regeneration

DESCRIPTION (provided by applicant): Tendons have poor healing ability and require surgical repair with grafts when ruptured. The grafts are fraught with problems ranging from failure to donor site morbidity, motivating stem cell-based tissue engineering strategies for tissue replacement. However, differentiation of cells toward the tendon lineage (tenogenesis) has been challenging due in part to a poor understanding of tendon development. Developmental biology studies have demonstrated that muscle plays a significant role in tendon embryogenesis, though the mechanisms of its contributions are not well understood because the respective physical (mechanical) and soluble signaling factor influences of muscle tissue have been difficult to study in a complex in vivo environment. Our objective is to identify and characterize muscle cell-produced soluble and mechanical tenogenic cues to direct tenogenesis. We hypothesize that soluble factors secreted by muscle cells, as a function of their developmental stage, will regulate tenogenesis of TPCs in vitro and that this process will be enhanced by dynamic mechanical stimulation. Using a unique in vitro co-culture system we will characterize muscle cell secretion of putative soluble factors and their potential tenogenic roles (Aim 1), and investigate the potential for mechanical loading to enhance chemoregulation by studying TGF22 as a model soluble factor (Aim 2). The outcomes of this study will subsequently be translated in a future study to develop a mesenchymal stem cell-based regeneration strategy through controlled application of these influences. Our long-range goal is to use developmental biology as motivation and a guide in developing novel mesenchymal stem cell-based strategies in regenerating new tissue to replace injured or diseased tendons and ligaments. The outcome of this research effort would significantly advance knowledge of tendon developmental biology, help define rational soluble factor dosing and mechanical loading parameters for progenitor cell differentiation, and lead to advanced strategies to engineer tendons with mesenchymal stem cells.

描述（申请人提供）：肌腱愈合能力差，断裂时需要用移植物进行手术修复。移植物充满了从失败到供体部位发病等问题，激发了基于干细胞的组织工程策略来进行组织替代。然而，细胞向肌腱谱系的分化（肌腱发生）一直具有挑战性，部分原因是对肌腱发育的了解不足。发育生物学研究表明，肌肉在肌腱胚胎发生中发挥着重要作用，尽管其贡献机制尚不清楚，因为肌肉组织各自的物理（机械）和可溶性信号因子影响很难在复杂的体内研究环境。我们的目标是识别和表征肌肉细胞产生的可溶性和机械性肌腱线索，以指导肌腱发生。我们假设肌肉细胞分泌的可溶性因子作为其发育阶段的函数，将在体外调节 TPC 的肌腱形成，并且该过程将通过动态机械刺激得到增强。使用独特的体外共培养系统，我们将表征推定可溶性因子的肌肉细胞分泌及其潜在的肌腱作用（目标 1），并通过研究 TGF22 作为模型可溶性因子来研究机械负荷增强化学调节的潜力（目标 2） ）。这项研究的结果随后将转化为未来的研究，通过控制这些影响的应用来开发基于间充质干细胞的再生策略。我们的长期目标是利用发育生物学作为动力和指导，开发基于间充质干细胞的新型策略，以再生新组织来替代受伤或患病的肌腱和韧带。这项研究工作的成果将显着增进对肌腱发育生物学的了解，帮助确定祖细胞分化的合理可溶性因子剂量和机械负荷参数，并产生用间充质干细胞改造肌腱的先进策略。

项目成果

Embryonic mechanical and soluble cues regulate tendon progenitor cell gene expression as a function of developmental stage and anatomical origin.

• DOI: 10.1016/j.jbiomech.2013.09.018
• 发表时间: 2014-01-03
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: Brown JP;Finley VG;Kuo CK
• 通讯作者: Kuo CK