Epidemiology of Connective Tissue Progenitor Populations

描述(由申请人提供)： 肌肉骨骼组织中含有数量非常少且具有异质性的干细胞和祖细胞，它们对结缔组织的修复和重塑具有持续的作用。我们已经为这些细胞定义并使用了包容性术语结缔组织前体细胞(CTPs)。CTP也是骨科组织工程工作的核心，既是细胞治疗的工具，也是局部和系统治疗的靶点。CTPs的最佳使用将需要了解(有时还需要控制)治疗部位的CTPs的浓度、流行率和生物学特性。它还需要最大限度地减少收获CTP所需的风险和努力。 这项建议的广泛目标是通过提供人松质骨中CTPs的流行病学和动力学以及CTPs的三种相关临床来源(抽吸骨髓、脂肪组织和肌肉)的定量表征，为组织工程和骨生物学领域做出贡献。我们还希望通过在将干细胞动力学与骨重建的经典组织形态计量学评估联系起来的数学模型的背景下，通过进一步发展和探索人类松质骨中的干细胞动力学来做出贡献。 松质骨核将从160名因骨关节炎接受选择性髋关节或膝关节置换术的患者身上获得。骨髓抽吸物、骨骼肌和皮下脂肪也将被收集。利用我们实验室开发的一套独特的定量工具，将通过菌落特异性分析来测量每个样本中CTPs的浓度、流行率和生物学性能。微计算机断层扫描和定量组织形态计量学将用于确定局部骨的结构、组织学和动态重塑环境。这些数据将结合起来确定CTP流行病学和骨髓间隙和骨小梁表面的动力学之间的关系，以及结构、组织学和动态骨重建活动。 这些数据将首次为外科医生和组织工程师提供有关人体组织中CTPs浓度、流行率和生物潜力的客观比较。这将使得能够合理地设计在人体组织中采集、浓缩、选择、移植或靶向CTPs的策略。 提出的策略还将提供一个工具和信息的量化平台，我们和其他研究人员可以在此基础上建立对人类结缔组织干细胞系统的更强有力的理解。这些数据将使探索、开发和评估与经典组织形态计量学参数相关联的骨骼重塑中干细胞激活和CTP动力学的定量理论模型成为可能。

DESCRIPTION (provided by applicant): Musculoskeletal tissues contain a very small and heterogeneous populations of stem cells and progenitor cells that contribute constantly to the repair and remodeling of connective tissues. We have defined and used the inclusive term Connective Tissue Progenitors (CTPs) for these cells. CTPs are also central to efforts in Orthopaedic Tissue Engineering, both as tools for cell therapy and as targets for local and systemic therapy. Optimal use of CTPs will require knowledge of (and sometimes control of) the concentration, prevalence and biologic characteristics of the CTPs in the site of treatment. It also requires minimizing the risk and effort needed for the harvest of CTPs. The broad aim of this proposal is to contribute to the field of tissue engineering and bone biology by providing a quantitative characterization of the epidemiology and kinetics of human CTPs in cancellous bone and three relevant alternative clinical sources of CTPs (aspirated bone marrow, fat tissue, and muscle). We also hope to contribute through further development and exploration stem cell kinetics in human cancellous bone in the context of a mathematical model linking stem cell kinetics with classic histomorphometry assessment of bone remodeling. Cores of cancellous bone will be harvested from 160 patients undergoing elective hip or knee replacement for osteoarthritis. Marrow aspirates, skeletal muscle and subcutaneous fat will also be collected. Using a unique set of quantitative tools developed in our laboratory, the concentration, prevalence and biologic performance of the CTPs in each sample will be measured using colony specific assays. Microcomputed tomography and quantitative histomorphometry will be used to define the structural, histologic and dynamic remodeling environment in the local bone. These data will be combined to define the relationship between CTP epidemiology and kinetics in the marrow space and on the trabecular surface, and structural, histologic and dynamic bone remodeling activity. These data will provide surgeons and tissue engineers, for the first time, with an objective comparison of the concentration, prevalence and biologic potential of the CTPs in relevant human tissues. This will enable the rational design of strategies for the harvest, concentration, selection, transplantation or targeting of CTPs in human tissues. The strategy proposed will also provide a quantitative platform of tools and information upon which we and other investigators can build a more robust understanding of the human connective tissue stem cell system. These data will enable exploration and development and assessment of a quantitative theoretical model of the kinetics of stem cell activation and CTP kinetics in skeletal remodeling that is linked to classic histomorphometric parameters.