Mechanisms of Skeletal Stem Cell Dysfunctions in Traumatic Bone Injuries

创伤性骨损伤中骨骼干细胞功能障碍的机制

• 批准号: 9921296
• 负责人: CELINE I COLNOT
• 金额: $ 30.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-12 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921296
• 关键词: Affect; Blood Vessels; Bone Injury; Bone Regeneration; Bone callus; Candidate Disease Gene; Cartilage; Cell Lineage; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Chondrocytes; Clinical; Crush Injury; Defect; Disease; Environment; FGF2 gene; Fracture; Fracture Healing; Functional disorder; Genetic; Goals; Heterogeneity; Human; IGF1 gene; Impairment; In Vitro; Injury; Knowledge; Lead; Limb structure; Modeling; Mus; Muscle; Muscle Cells; Muscle satellite cell; Musculoskeletal Diseases; Open Fractures; Osteoblasts; Patients; Periosteal Cell; Periosteum; Phenotype; Physiologic Ossification; Play; Population; Process; Role; Signal Transduction; Site; Soft Tissue Injuries; Source; Surgical Flaps; System; Testing; Therapeutic; Tibial Fractures; Time; Tissue Grafts; Tissues; Trauma; Traumatic injury; Work; base; bone; bone healing; design; disability; experimental study; fracture risk; healing; improved; in vivo; infection risk; inflammatory milieu; musculoskeletal injury; novel therapeutic intervention; novel therapeutics; progenitor; recruit; regenerative; repaired; response; satellite cell; severe injury; single-cell RNA sequencing; skeletal; stem; stem cells; tool; transcriptome sequencing; transdifferentiation; vascular injury

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.

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