Species-specific and Systems Biology Approach to MSC-based Therapies

描述(申请人提供)：骨髓间充质干细胞(MSCs)目前正在180多个公开临床试验中进行评估，用于治疗各种人类疾病。尽管MSCs在临床治疗中的使用越来越多，但许多基于MSC的临床试验未能达到其疗效的主要终点，基于体外或实验动物模型进行的细胞潜能研究，对患者结局的预测也很差。事实上，缺乏关于MSC群体功能复杂性的知识，缺乏指定有助于细胞潜能的细胞行为的途径，以及这些途径中的物种差异，是开发优化和可预测的临床治疗的主要障碍。为了克服这些限制，这项建议将比较和对比啮齿动物和人类间充质干细胞基础生物学的物种差异，确定影响细胞潜能的不同生物功能在种群中是如何指定的，并展示调节基础细胞生物学和非祖细胞功能的途径之间的功能联系。为了提高临床前动物模型的价值，该实验室还将创建来自不同近亲繁殖、转基因和敲除小鼠品系的MSCs的储存库，并将这些细胞提供给更广泛的科学界。用来生产细胞的方法产生了非永生化的、非克隆的群体，概括了人类MSCs的功能复杂性和行为。因此，它们的使用提供了一种手段，以标准化跨实验室和不同实验动物模型之间的生物学和翻译研究，从而增加啮齿动物模型在临床领域预测细胞行为的价值。

DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) are currently being evaluated in over 180 open clinical trials for the treatment of a variety of human diseases. Despite the growing use of MSCs in clinical therapy, many MSC-based clinical trials have failed to meet their primary endpoint of efficacy and patient outcomes have been poorly predicted based on cell potency studies conducted in vitro or in experimental animal models. Indeed, lack of knowledge regarding the functional complexity of MSC populations, pathways that specify cellular behaviors that contribute to cell potency, and species differences in these pathways represent a major impediment toward developing optimized and predictable clinical therapies. To overcome these limitations, this proposal will compare and contrast species differences in the basic biology of rodent and human MSCs, determine how different biological functions that affect cell potency are specified within populations, and demonstrate a functional link between pathways that regulate basic cell biology and non-progenitor functions. To enhance the value of pre-clinical animal models, this laboratory will also create a repository of MSCs from different inbred, transgenic, and knockout strains of mice and supply these cells to the greater scientific community. Methods used to produce cells yield non-immortalized, non-clonal populations that recapitulate the functional complexity and behavior of human MSCs. Consequently, their use provides a means to standardize biological and translational studies across laboratories and between different experimental animal models, thereby augmenting the value, of rodent models for predicting cellular behaviors in the clinical arena.