Structural microenvironment of bone marrow stem cells

骨髓干细胞的结构微环境

• 批准号: 8708764
• 负责人: Francesco B Ramirez
• 金额: $ 18.01万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708764
• 关键词: Ablation; Accounting; Address; Adult; Affect; Age-Related Bone Loss; Animals; Aortic Diseases; Behavior; Binding; Biological Availability; Blood; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone remodeling; Calibration; Cardiovascular Abnormalities; Cartilage; Cell Communication; Cell Differentiation process; Cell Maintenance; Cell Therapy; Cells; Clinical Management; Complex; Connective Tissue Diseases; Defect; Deformity; Deposition; Development; Disease Progression; Event; Extracellular Matrix; Extracellular Matrix Proteins; FBN1; Family; Fracture; Future; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Immune; Immune system; Inflammatory Response; Integrins; Investigation; Knowledge; Lead; Life; Marfan Syndrome; Marrow; Mediating; Medical; Mesenchymal; Mesenchymal Stem Cells; Mus; Mutate; Mutation; Osteogenesis; Osteopenia; Pathogenesis; Performance; Population; Production; Proteins; Publishing; Regenerative Medicine; Regulation; Research Priority; Role; Signal Transduction; Skeleton; Specific qualifier value; Stem cells; Stromal Cells; Structure; Supporting Cell; Testing; Therapeutic; Tissue Engineering; Tissues; adult stem cell; age related; base; body system; bone; bone loss; cell type; high reward; high risk; human disease; improved; innovation; insight; loss of function mutation; mouse model; mutant; nestin protein; novel; physical property; preconditioning; premature; public health relevance; receptor; reconstitution; research study; skeletal; skeletal tissue; stem cell biology; stem cell differentiation; stem cell niche; tissue regeneration

DESCRIPTION (provided by applicant): The definition of adult stem cell niches in the bone marrow (BM) and their regulation by extrinsic factors is a top research priority in tissue engineering and skeletal regenerative medicine, as well as a critical aspect of hematopoietic function and its reconstitution after marrow ablation therapy. Unlike the wealth of information regarding the cell types, cell-cell interactions and soluble signals that specify functionally discrete BM microenvironments, significantly less is known about the role of the extracellular matrix (ECM) in niche function to the detriment of developing more effective stem cell-based therapies. Our preliminary findings are the first to indicate involvement of fibrillin-1, a unique ECM protein that regulates the spatial organization and physical properties of tissues as well as the bioavailability of endogenous (local) TGF¿ family signals. This discovery raises the exciting possibility that a structural component of the marrow matrix controls the production of bone, blood and immune cells by determining the physical microenvironment of resident stem cells and by coordinating regulatory signals within it. Fibrillin-1 is the mutated protein in Marfan syndrome (MFS), whose pleiotropic manifestations include progressive bone loss (osteopenia). We previously demonstrated that osteopenia in MFS mice reflects perturbed bone remodeling due to impaired calibration of local anabolic and catabolic signals. Ongoing investigations have implied that fibrillin-1 is an essential component of the BM microenvironment that specifies the performance of mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC). The goal of this high risk/high reward R21 application is to answer the following two questions: (a) What are the phenotypic consequences of fibrillin-1 deficiency for BM-based osteogenesis and hematopoiesis? ; (b) Does fibrillin-1 coordinate MSC-supported HSC performance? Accordingly, we propose to: (Aim 1) Characterize impaired MSC activity and bone loss progression in mice lacking fibrillin-1 in the appendicular skeleton and to provide a full account of hematopoietic abnormalities in these mutant animals; and (Aim 2) Validate the role of fibrillin-1 in coordinating MSC-supported HSC differentiation using mice with conditional Fbn1 inactivation in a specific stromal cells population. By demonstrating that fibrillin-1 is an indispensable functional component of BM niches, the experiments will establish the basis for future interrogation of the mechanism mediating fibrillin-1 regulation of marrow niches; and by implicating fibrillin-1 in immune system function, they may also lead to a radically new understanding of the cellular events responsible for aortic disease progression in MFS with unanticipated opportunities for therapy. Overall, this highly innovative proposal is expected to yield novel insights into age-related bone loss, advance fundamental knowledge of stem cell biology, impact a variety of translational applications in regenerative medicine, and perhaps improve the clinical management of life- threatening aortic manifestations in MFS.

描述（通过应用提供）：骨髓（BM）中成年干细胞生态位的定义及其对外部因素的调节是组织工程和骨骼再生医学的最佳研究优先级，以及造血功能的关键方面及其在玛格育育治疗后重新结束的关键方面。与有关细胞类型的丰富信息，细胞 - 细胞相互作用和实体信号的丰富信息不同，在功能上具有离散的BM微环境，对细胞外基质（ECM）在利基功能中的作用的了解明显较小，以确定开发更有效的干细胞疗法。我们的初步发现是第一个表明Fibrillin-1的参与，Fibrillin-1是一种独特的ECM蛋白，可调节组织的空间组织和物理性质以及内源性（局部）TGF tgfqu的生物利用度。这一发现增加了令人兴奋的可能性，即通过确定居民干细胞的物理微环境以及其中的配位调节信号，骨髓基质的结构成分控制骨，血液和免疫细胞的产生。 Fibrillin-1是Marfan综合征（MFS）中突变的蛋白质，其多效性表现包括进行性骨质流失（骨质骨减少症）。我们先前证明，MFS小鼠中的骨质减少症反映出由于局部合成代谢和分解代谢信号的校准受损而导致的骨骼重塑。正在进行的研究表明，Fibrillin-1是BM微环境的重要组成部分，它指定了间充质干细胞（MSC）和造血干细胞（HSC）的性能。这种高风险/高奖励R21应用的目的是回答以下两个问题：（a）纤维蛋白-1缺乏症对基于BM的成骨和造血的表型后果是什么？ （b）纤维蛋白-1是否协调MSC支持的HSC性能？根据，我们建议：（ AIM 1）表征阑尾骨骼中缺乏纤维蛋白-1的小鼠MSC活性和骨质流失进展的表征，并提供了这些突变动物中造血异常的完整说明； （目标2）验证纤维蛋白-1在协调中的作用 在特定基质细胞种群中，使用小鼠与有条件的FBN1失活的小鼠相支持的HSC分化。通过证明Fibrillin-1是BM壁ches的必不可少的功能成分，实验将为介导骨髓壁ches的Fibrillin-1调节机制的未来询问建立基础。通过隐式纤维素-1在免疫系统功能中，它们也可能导致对导致主动脉疾病进展的细胞事件的根本性理解，并具有意外的治疗机会。总体而言，这一高度创新的提案有望产生对与年龄相关的骨质流失，干细胞生物学的提前基本知识的新见解，影响再生医学中的各种翻译应用，并可能改善对MFS中主动脉症的临床管理的临床管理。