Deciphering multi-scale differentiation and patterning cues driving whole craniofacial joint regeneration

项目摘要 关节损伤和疾病是全世界残疾的主要原因。滑膜关节由以下组成 复杂和结构完整的组织，包括专门润滑关节软骨和结缔组织 稳定关节运动的韧带等组织。在哺乳动物中，关节组织的愈合能力很差。甚至 重建手术后，韧带不能重建未受伤关节的生物力学特性， 再次损伤或退行性关节疾病风险高的患者。这种有限的愈合能力是由于 分化涉及瘢痕组织的发展，而不是成熟的韧带细胞和软骨细胞 血统目前，我们对驱动谱系的潜在分子线索的理解有限 功能最关键的关节细胞类型，特别是关节软骨和韧带的规格。为了 为关节组织的再生医学治疗设计改进的策略，该项目将利用 在高度再生的斑马鱼中独特的全关节再生模型。虽然关节损伤无法愈合， 在哺乳动物模型中，我们发现内源性骨骼祖细胞能稳健地再生滑膜关节组织， 在斑马鱼遭受灾难性伤害之后新的关节与周围组织整合，以恢复生物力学 功能重要的是，这种高再生能力包括新的润滑关节软骨的分化 和完全整合的新关节支撑韧带。在这里，通过结合遗传和空间分析，我们 将识别和功能解剖祖细胞的潜在分子调控，并表征其 与它们各自的再生小生境的物理相互作用需要再生复杂的3D关节组织。 这种高风险/高回报的建议将对我们对关节再生的理解产生广泛的影响 通过内源性细胞来源的修复，并为整个关节提供改进的组织工程方法 关节疾病的替代。

PROJECT SUMMARY Joint injuries and diseases are the leading causes of disability worldwide. Synovial joints are composed of complex and structurally integrated tissues, including specialized lubricating articular cartilage and connective tissues like ligaments that stabilize joint movement. In mammals, joint tissues have a poor healing capacity. Even after reconstructive surgery, ligaments fail to reestablish the biomechanical properties of uninjured joints, leaving patients at high risk for re-injury or degenerative joint disease. This limited healing capacity results from a failure of differentiation involving the development of scar tissue in place of mature ligamentocyte and chondrocyte lineages. Currently, we have a limited understanding of the underlying molecular cues that drive lineage specification of the most functionally critical joint cell types, particularly articular cartilage and ligaments. In order to devise improved strategies for regenerative medicine therapeutics for joint tissues, this project will leverage a unique whole joint regeneration model in the highly regenerative zebrafish. While joint injuries fail to heal in mammalian models, we find that endogenous skeletal progenitor cells robustly regenerate synovial joint tissues after a catastrophic injury in zebrafish. The new joint integrates with surrounding tissues to restore biomechanical function. Critically, this high regenerative capacity includes the differentiation of new lubricating articular cartilage and fully integrated new joint-supporting ligaments. Here, through combined genetic and spatial analyses, we will identify and functionally dissect the underlying molecular regulation of progenitors and characterize their physical interactions with their respective regenerative niches required to regenerate complex 3D joint tissues. This high-risk/high-reward proposal will have wide-ranging impacts on our understanding of joint regeneration via repair from endogenous cell sources and inform improved tissue engineering approaches to whole joint replacement in joint disease.