Mechanisms of Skeletal Stem Cell Dysfunctions in Traumatic Bone Injuries

项目总结： 肌肉骨骼疾病和紊乱是致残的第二大原因，也是一个重要原因。 世界范围内的临床负担。在这些疾病中，肌肉骨骼损伤可导致 大约10%的骨折病例，延迟愈合或不愈合的风险增加到 合并软组织和血管损伤时占46%。而肌肉被认为扮演着重要的角色 在骨愈合方面，其作用机制仍然知之甚少。我们的知识有很大的差距 了解肌肉-骨骼串扰在骨修复中调节骨骼干细胞功能的作用。我们的目标是 在一种新的肌肉-骨损伤中阐明肌肉损伤导致骨愈合受损的机制 反映人类创伤性损伤的小鼠模型。在这个模型中，肌肉挤压伤严重影响骨骼。 通过推迟愈伤组织的形成和干细胞的募集来修复。我们设计了多个实验 基于体外实验的方法，用于谱系分析和组织分析的最先进的遗传工具 移植实验，以确定该模型中创伤性损伤影响的程度 骨骼和邻近肌肉中骨骼干细胞的协调激活和分化。通过这些 方法，我们将具体确定骨骼干细胞从肌肉和 骨折骨痂中的骨膜(目标1)，表征肌肉和骨组织中受损的骨骼干细胞激活 创伤性损伤环境中的骨膜(目标2)及创伤性损伤对软骨向骨转化的影响 骨再生过程中的转化(目标3)。我们的工作将有助于确定工会不团结的原因 与多发性创伤有关，并可能导致治疗创伤的新的药物或细胞疗法 肌肉骨骼损伤和骨骼愈合延迟。

Project Summary: Musculoskeletal diseases and disorders represent the second leading cause of disability and are a significant clinical burden worldwide. Among these disorders, musculoskeletal injuries can lead to complications in approximately 10% of the cases of bone fractures, and the risk of delayed- or non-union is increased up to 46% when associated with soft tissue and vascular injuries. While muscle is thought to play an important role in bone healing, the mechanisms of action remain poorly understood. There is a large knowledge gap in our understanding of muscle-bone crosstalk in regulating skeletal stem cell function in bone repair. We aim to elucidate the mechanisms by which muscle injury leads to impaired bone healing in a new muscle-bone injury model in mice that reflects traumatic injury in human. In this model, muscle crush injury severely impacts bone repair by delaying callus formation and stem cell recruitment. We have designed multiple experimental approaches, based on in vitro experiments, state-of-the-art genetic tools for lineage analyses and tissue grafting experiments in order to determine the extent to which traumatic injury in this model affects the coordinated activation and differentiation of skeletal stem cells in bone and adjacent muscle. Through these approaches, we will specifically identify the mechanisms of skeletal stem cell recruitment from muscle and periosteum in the fracture callus (aim 1), characterize the impaired skeletal stem cell activation in muscle and periosteum in the traumatic injury environment (aim 2) and the impact of traumatic injury on cartilage-to-bone transformation during bone regeneration (aim 3). Our work will help determine the causes of non-union associated with polytrauma and may lead to new drug- or cell-based therapies to treat traumatic musculoskeletal injuries and delayed bone healing.