Mechanisms of Skeletal Stem Cell Dysfunctions in Traumatic Bone Injuries

项目概要： 肌肉骨骼疾病和紊乱是残疾的第二大原因， 全球临床负担。在这些疾病中，肌肉骨骼损伤可导致并发症， 约10%的骨折病例，延迟愈合或不愈合的风险增加至 46%与软组织和血管损伤有关。虽然肌肉被认为在 在骨愈合中，作用机制仍然知之甚少。我们的知识差距很大。 了解骨骼修复中调节骨骼干细胞功能的肌肉-骨骼串扰。我们的目标是 阐明肌肉损伤导致新的肌肉-骨损伤中骨愈合受损的机制 反映人类创伤性损伤的小鼠模型。在该模型中，肌肉挤压损伤严重影响骨骼 通过延迟愈伤组织形成和干细胞募集来修复。我们设计了多个实验 方法，基于体外实验，最先进的遗传工具，用于谱系分析和组织 移植实验，以确定在该模型中创伤性损伤影响移植物的程度。 协调骨骼和邻近肌肉中的骨骼干细胞的活化和分化。通过这些 方法，我们将具体确定骨骼干细胞从肌肉招募的机制， 骨折骨痂中的骨膜（目的1），表征肌肉中受损的骨骼干细胞活化， 创伤性损伤环境中的骨膜（目的2）和创伤性损伤对软骨-骨的影响 骨再生过程中的转化（目的3）。我们的工作将有助于确定不团结的原因 与多发性创伤相关，并可能导致新的药物或细胞为基础的治疗创伤 肌肉骨骼损伤和骨愈合延迟。

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.