Epidemiology of Connective Tissue Progenitor Populations

描述（由申请人提供）： 肌肉骨骼组织含有非常小且异质的干细胞和祖细胞群体，其不断地有助于结缔组织的修复和重塑。我们已经为这些细胞定义并使用了包含性术语结缔组织祖细胞（CTPs）。 CTP也是骨科组织工程的核心，既作为细胞治疗的工具，也作为局部和全身治疗的靶点。 最佳使用CTP将需要了解（有时控制）治疗部位CTP的浓度、流行率和生物学特征。 它还要求最大限度地减少现金转拨方案收获所需的风险和努力。 该提案的主要目的是通过提供松质骨中人类CTP的流行病学和动力学的定量表征以及CTP的三种相关替代临床来源（抽吸骨髓、脂肪组织和肌肉），为组织工程和骨生物学领域做出贡献。 我们还希望通过进一步开发和探索干细胞动力学在人类松质骨的数学模型的背景下，连接干细胞动力学与骨重建的经典组织形态计量学评估作出贡献。 将从160名因骨关节炎接受择期髋关节或膝关节置换术的患者中采集松质骨核心。 还将采集骨髓穿刺液、骨骼肌和皮下脂肪。 使用我们实验室开发的一套独特的定量工具，将使用菌落特异性测定法测量每份样本中CTP的浓度、流行率和生物学性能。 将使用显微计算机断层扫描和定量组织形态学来确定局部骨的结构、组织学和动态重塑环境。 将结合这些数据，以确定CTP流行病学和骨髓腔和骨小梁表面动力学与结构、组织学和动态骨重建活性之间的关系。 这些数据将首次为外科医生和组织工程师提供相关人体组织中CTP的浓度，流行率和生物学潜力的客观比较。 这将使得能够合理设计用于人类组织中CTP的收获、浓缩、选择、移植或靶向的策略。 提出的策略还将提供一个工具和信息的定量平台，在此基础上，我们和其他研究人员可以对人类结缔组织干细胞系统建立更强大的理解。这些数据将使探索和开发和评估的定量理论模型的干细胞活化的动力学和CTP动力学在骨骼重塑，是与经典的组织形态学参数。

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.