Redefining mesenchymal stem cells: using their cellular and molecular phenotypes to determine their regenerative and therapeutic properties

摘要 间充质干细胞（MSC）在再生医学细胞疗法中具有广泛的潜力， 可以从各种不同的组织中分离。尽管不同组织的MSCs在表型上 类似地，其临床应用的障碍是其营养和再生特性的高度可变性。这 变异性表明，在指导MSC特性的分子机制中存在固有差异 然而，迄今为止，这些差异是不明确的。为此我们 初步证据表明MSC表型与其再生结果相关。在这项研究中，我们的目标是 为了阐明不同MSC群体的分子和细胞特性如何决定其 再生性能我们的假设是，不同组织来源的MSCs具有不同的再生能力， 与由基因表达和转录定义的特定分子谱相关的性质 活动为了验证这一假设，拟议的项目有三个具体目标（SA）。在SA1中，我们将 确定组织特异性如何决定基因表达和动态转录因子活性 不同的MSC。SA2将确定细胞和分子特性的差异， MSC与MSC表型相关。最后，在SA3中，我们将确定分子概况和 MSC的细胞活性决定了它们的再生特性。拟议研究的结果将 提供了关于MSC的不同分子谱如何决定其生物学和生物学特性的新见解， 生理特性在治疗方面，这将有助于开发创新的 MSC疗法的筛选技术，以鉴定和富集最适合的MSC， 具体的治疗应用。

ABSTRACT Mesenchymal stem cells (MSCs) have broad-based potential in regenerative medicine cell therapies and can be isolated from a variety of different tissues. Though MSCs from different tissues are phenotypically similar, a barrier to their clinical use is the high variability of their trophic and regenerative properties. This variability suggests that inherent differences exist in the molecular machinery guiding MSC properties between different MSC populations, yet, to date, these differences are ill-defined. To this end, we have preliminary evidence that MSC phenotypes correlate to their regenerative outcomes. In this study, we aim to elucidate how the molecular and cellular properties of distinct MSC populations determine their regenerative properties. Our hypothesis is that MSCs from different tissues have different regenerative properties which correlate to specific molecular profiles defined by gene expression and transcriptional activity. To test this hypothesis, the project proposed has three Specific Aims (SAs). In SA1, we will determine how tissue-specificity dictates gene expression and dynamic transcription factor activity of distinct MSCs. SA2 will determine how differences in the cellular and molecular properties of MSCs correlate to MSC phenotype. Finally, in SA3, we will determine how the molecular profiles and cellular activities of MSCs dictate their regenerative properties. Findings of the proposed study will provide novel insights about how the distinct molecular profiles of MSCs dictate their biological and physiological properties. In a therapeutic context, this would enable the development of innovative screening technologies for MSC therapies to identify and enrich for the most appropriate MSC for the specific therapeutic application.