Structural microenvironment of bone marrow stem cells

骨髓干细胞的结构微环境

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：骨髓（BM）中成体干细胞巢的定义及其受外在因素的调节是组织工程和骨骼再生医学的首要研究重点，也是造血功能和骨骼再生的一个关键方面。与骨髓消融治疗后其重建的大量信息不同，有关细胞类型、细胞间相互作用和可溶性信号指定功能离散的骨髓微环境的信息明显较少。我们的初步研究结果首次表明，fibrillin-1（一种调节组织空间组织和物理特性的独特 ECM 蛋白）参与其中。以及内源性（局部）TGF 的生物利用度¿这一发现提出了一个令人兴奋的可能性，即骨髓基质的结构成分通过确定常驻干细胞的物理微环境并通过协调其中的 Fibrillin-1 调节信号来控制骨骼、血液和免疫细胞的产生。马凡综合征（MFS）中的蛋白质，其多效性表现包括进行性骨质流失（骨质减少），我们之前证明，MFS 小鼠的骨质减少反映了由于局部合成代谢和校准受损而导致的骨重塑紊乱。正在进行的研究表明，fibrillin-1 是 BM 微环境的重要组成部分，它决定了间充质干细胞 (MSC) 和造血干细胞 (HSC) 的性能。这种高风险/高回报的 R21 应用的目标是。回答以下两个问题：(a) fibrillin-1 缺乏对基于 BM 的成骨和造血有什么表型后果？ fibrillin-1 协调 MSC 支持的 HSC 性能？因此，我们建议：（目标 1）表征阑尾骨骼中缺乏 fibrillin-1 的小鼠的 MSC 活性受损和骨质流失进展，并提供这些突变体中造血异常的完整说明动物；以及（目标 2）验证 fibrillin-1 在协调中的作用使用在特定基质细胞群中条件性 Fbn1 失活的小鼠进行 MSC 支持的 HSC 分化通过证明 fibrillin-1 是 BM 生态位不可或缺的功能成分，该实验将为未来探究介导 fibrillin-1 调节的机制奠定基础。骨髓生态位的研究；并且通过将 fibrillin-1 与免疫系统功能联系起来，它们还可能导致对导致主动脉疾病的细胞事件产生全新的认识总体而言，这一高度创新的提议有望对与年龄相关的骨质流失产生新的见解，推进干细胞生物学的基础知识，影响再生医学的各种转化应用，并可能改善MFS 中危及生命的主动脉表现的临床管理。