Regulation of human tendon development and regeneration

人体肌腱发育和再生的调节

• 批准号: 10681951
• 负责人: Alice H Huang
• 金额: $ 64.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681951
• 关键词: Address; Adopted; Adult; Affect; Atlases; Automobile Driving; Biology; Cartilage; Cells; ChIP-seq; Chromatin; Cicatrix; Clinical; Data Set; Development; Embryo; Engraftment; Enhancers; Exhibits; Failure; Fatty acid glycerol esters; Genetic Transcription; Human; Immobilization; Immune; Immune response; Immunodeficient Mouse; Impairment; In Situ Hybridization; In Vitro; Injury; Knowledge; Label; Large-Scale Sequencing; Macrophage; Mediating; Mesenchymal; Modeling; Molecular; Multipotent Stem Cells; Mus; Myofibroblast; Natural regeneration; Outcome; Pain; Pathologic; Phenotype; Population; Regenerative capacity; Regenerative pathway; Regulation; Source; Standard Model; Structure; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Therapeutic; Time; Transcriptional Regulation; achilles tendon; clinically relevant; design; differentiation protocol; effective therapy; epigenetic regulation; experimental study; functional restoration; healing; human embryonic stem cell; improved; in vivo; induced pluripotent stem cell; knock-down; loss of function; multiple omics; mutant; novel; novel therapeutics; paracrine; prevent; progenitor; recruit; regeneration potential; regenerative; regenerative cell; repaired; single-cell RNA sequencing; small hairpin RNA; stem; stem cells; tendon development; tendon rupture; transcription factor; translational potential

PROJECT SUMMARY After injury, tendon function is often compromised due to poor healing and failure to regenerate native structure. Due to limited treatment options, there is an unmet clinical need for effective therapies that promote tendon healing and functional restoration. However, our incomplete understanding of tendon biology prevents the design of therapeutics that activate regenerative pathways involved in tendon formation. In particular, two major obstacles exist: (1) the critical regulators of tendon induction and differentiation are unknown and (2) the regulators driving non-regenerative adult tendon healing have not been elucidated or overcome. While the mouse is the gold standard model to study the biology of mammalian tendon development and healing, the extent of its relevance to human is unclear. To address these questions, we established robust differentiation protocols to derive tenocytes from mouse embryonic stem cells (mESCs) and human induced pluripotent stem cells (hiPSCs). Using these in vitro tendon differentiation models in combination with human and mouse embryos, clinically relevant injury models, and multiomics approaches, we will determine transcriptional and epigenetic regulation of tendon cell fate in the contexts of development and injury.

项目总结 肌腱损伤后，由于愈合不良和不能再生天然结构，肌腱功能经常受到影响。 由于治疗选择有限，临床上对促进肌腱的有效疗法的需求尚未得到满足。 愈合和功能恢复。然而，我们对肌腱生物学的不完全理解阻碍了这一设计 激活与肌腱形成有关的再生通路的治疗方法。特别是，有两个主要的 障碍存在：(1)肌腱诱导和分化的关键调控因子未知；(2)肌腱诱导和分化的关键调控因子 驱动非再生性成人肌腱愈合的调节因素尚未阐明或克服。而当 小鼠是研究哺乳动物肌腱发育和愈合生物学的金标准模型， 它与人类的相关性程度尚不清楚。为了解决这些问题，我们建立了稳健的差异化 从小鼠胚胎干细胞和人诱导的多能干细胞中获取腱细胞的方案 细胞(HiPSCs)。将这些体外肌腱分化模型与人和小鼠结合使用 胚胎、临床相关损伤模型和多组学方法，我们将确定转录和 肌腱细胞在发育和损伤过程中命运的表观遗传调控。