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

• 批准号: 8919847
• 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
• 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/8919847
• 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; Image; 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; 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

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）：骨谱系细胞在骨的终身再生过程中特别重要。它们在骨髓微环境中也是至关重要的，在那里它们控制造血，并可能参与白血病和癌症转移。然而，尽管成骨细胞在维持骨骼和造血中起着关键作用，但这些细胞的体内起源、寿命和动力学仍然是根本上没有答案的问题。因此，我们的目的是确定骨形成成骨细胞的寿命和它们在稳态和损伤条件下的替代来源。我们最近的研究使用基因脉冲追踪技术结合延时活体动物荧光成像显示，功能性成骨细胞和成骨细胞前体细胞的寿命很短，并持久地维持其祖细胞在体内。此外，我们发现“间充质干细胞”（如体外多谱系能力所定义的）在体内没有这种功能。相反，它们在正常的体内平衡中充当骨谱系限制性祖细胞。这些成骨祖细胞可以通过粘病毒抗性-1（Mx 1）启动子的瞬时激活进行遗传标记。我们证明Mx 1标记的成骨祖细胞来源于血管周围，能有效地迁移到损伤部位，并为血管周围的成骨细胞提供营养。 大多数新的成骨细胞在骨折愈合。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，可以标记成骨干细胞/祖细胞，前成骨细胞和成熟成骨细胞。本研究的目的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。我们还将探讨成骨干细胞的临床相关性，目的是逆转退行性骨疾病的条件。因此，我们建议：1.检测Mx 1和巢蛋白双标记是否能在体内特异性标记成骨干细胞。 2.成骨干细胞移植能否促进骨折愈合的实验研究。 3.测试成骨干细胞在骨丢失疾病中的作用。通过研究三个具体的，临床相关的问题，我们将进一步确定新的生物学和生理条件下的成骨干细胞的临床见解。