Role of osteogenic stem cells in bone regeneration and repair in vivo

成骨干细胞在体内骨再生和修复中的作用

基本信息

批准号：
9116096
负责人：
Dongsu Park
金额：
$ 13.18万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116096
关键词：
Adipocytes Age-Related Bone Loss Animals Biological Bone Diseases Bone Injury Bone Marrow Bone Marrow Diseases Bone Matrix Bone Regeneration Cell Cycle Kinetics Cell Lineage Cells Characteristics Chondrocytes Clinical Degenerative Disorder Disease Disease Progression Fracture Fracture Healing Genes Genetic Genetically Engineered Mouse Goals Health Hematopoiesis Hematopoietic Hematopoietic stem cells Homeostasis In Vitro Inherited Injury Label Life Longevity Maintenance Maps Mesenchymal Mesenchymal Stem Cells Modeling Molecular Myxovirus Nature Neoplasm Metastasis Osteoblasts Osteocytes Osteoporosis Pathway interactions Pericytes Phenotype Physiologic pulse Physiological Play Population Process Proliferating Recovery Regulation Reporter Resistance Role Series Site Skeleton Source Specific qualifier value Staging Stem Cell Development Stem cell transplant Stem cells Stress Surface Techniques Testing Therapeutic Time Tissues Transplantation base bone bone cell bone loss cellular targeting clinically relevant fluorescence imaging improved in vivo in vivo imaging insight intravital microscopy leukemia meetings mouse model nestin protein osteogenic osteoprogenitor cell progenitor promoter regenerative repaired research study response to injury restoration skeletal skeletal regeneration stem tissue regeneration tissue repair

项目摘要

DESCRIPTION (provided by applicant): Osteo-lineage cells are of particular importance in the life-long regenerative processes of bone. They are also critical in the bone marrow microenvironment where they control hematopoiesis and likely participate in leukemia and cancer metastasis. However, despite the pivotal roles of osteogenic cells in the maintenance of bones and hematopoiesis, the in vivo origin, lifespan, and dynamics of these cells remain fundamentally unanswered questions. Therefore, we aimed to define the lifespan of bone-forming osteoblasts and their source of replacement under homeostatic and injury conditions. Our recent studies using genetic pulse-chase techniques in combination with time-lapse live-animal fluorescent imaging have revealed that functional osteoblasts and osteoblast precursors have a short lifespan and are durably maintained by their progenitor cells in vivo. Additionally, we found that the 'mesenchymal stem cells' (as defined by in vitro multilineage capacity) have no such function in vivo. Rather, they serve as osteolineage-restricted progenitors in normal homeostasis. These osteogenic progenitors can be genetically marked by transient activation of the myxovirus resistance-1 (Mx1) promoter. We demonstrated that Mx1-labeled osteogenic progenitor cells have a perivascular origin, migrate efficiently to sites of injury, and supply the majority of new osteoblasts in fracture healing. Further, they overlap with a subset of perivascular nestin� MSCs. We now have distinct stage-specific inducible models that can label osteogenic stem/progenitors, pre-osteoblasts and mature osteoblasts. The goal of this study is to understand the role of mature osteoblasts and their stem/progenitor cells in the context of bone regeneration and repair in vivo. We will also explore the clinical relevance of osteogenic stem cells with the goal of reversing conditions of degenerative bone disease. We thus propose to: 1. Test if Mx1 and nestin double labeling specify osteogenic stem cells in vivo. 2. Test if te transplantation of osteogenic stem cells improves the restoration of bone fracture. 3. Test the role of osteogenic stem cells in bone loss diseases. By studying three specific, clinically relevan questions, we will further define new biological and clinical insights of osteogenic stem cells in physiological conditions.

描述（由申请人提供）：骨谱系细胞在骨骼的终生再生过程中特别重要，它们在控制造血并可能参与白血病和癌症转移的骨髓微环境中也至关重要。成骨细胞在维持骨骼和造血功能中的关键作用、这些细胞的体内起源、寿命和动力学仍然是根本上未解答的问题，因此，我们的目的是定义成骨细胞。我们最近使用遗传脉冲追踪技术结合延时活体动物荧光成像进行的研究表明，功能性成骨细胞和成骨细胞前体细胞的寿命很短，并且在稳态和损伤条件下的替代来源。此外，我们发现“间充质干细胞”（由体外多谱系能力定义）在体内没有这种功能。作为正常体内平衡中的骨谱系限制性祖细胞，这些成骨祖细胞可以通过粘病毒抵抗-1（Mx1）启动子的瞬时激活进行遗传标记，我们证明Mx1标记的成骨祖细胞具有血管周围起源，可以有效地迁移到损伤部位。，并提供此外，它们与血管周围巢蛋白 MSC 的子集重叠。我们现在有不同的阶段特异性诱导模型，可以标记成骨干/祖细胞、前成骨细胞和成熟成骨细胞。我们的目标是了解成熟成骨细胞及其干/祖细胞在体内骨再生和修复中的作用，我们还将探索成骨干细胞的临床相关性。因此，我们建议： 1. 测试 Mx1 和巢蛋白双标记是否在体内指定成骨干细胞 2. 测试成骨干细胞移植是否可以改善骨折的恢复。成骨干细胞在骨质流失疾病中的作用通过研究三个具体的临床相关问题，我们将进一步确定成骨干细胞在生理条件下的新生物学和临床见解。