Mesenchymal Stem Cells and the Microenvironment

描述（由申请人提供）：人间充质干细胞（MSC）是多能干细胞，可分化为人体肌肉骨骼和基质组织中的许多细胞，包括成纤维细胞、软骨细胞、成骨细胞、肌细胞和脂肪细胞。虽然间充质干细胞分化成适当的谱系可能会促进受损组织的愈合，但不适当的谱系规范可能会导致许多病理生理过程，包括骨质疏松性骨骼中骨量的减少和脂肪的增加，以及动脉粥样硬化血管壁的钙化。因此，局部微环境因素对间充质干细胞谱系承诺的调节可能对于我们对许多退行性和愈合过程的基本理解至关重要。这项研究的长期目标是表征局部周围微环境中驱动人类间充质干细胞 (MSC) 谱系规范和分化的线索以及所涉及的分子途径。研究人员发现，间充质干细胞与纤连蛋白的粘附通过涉及 RhoA 信号传导和细胞骨架张力的机制，调节间充质干细胞在成脂和成骨谱系规范之间的定向转换。在过去的资助期间，他证明了这些粘附和机械信号特异性调节 SMAD 和 PPARgamma，这两个对成骨和脂肪生成至关重要的关键转录因子。具体目标 1 是研究整合素激活如何调节 BMP-SMAD 信号传导和成骨。具体目标 2 是研究 RhoA 如何调节 SMAD 活性。具体目标 3 将是研究粘附和机械信号如何调节 PPARgamma 信号传导。这些研究将共同​​确定细胞粘附、RhoA 和细胞骨架张力在 MSC 谱系定型中的作用，并为微环境线索调节 MSC 分化奠定分子基础。 公共健康相关性：人类间充质干细胞有助于许多肌肉骨骼组织的维持和愈合，但它们也可能产生不适当的细胞谱系，从而加剧疾病，例如动脉粥样硬化血管钙化所发生的情况。它们现在被分离出来，作为再生疗法的干细胞的有前途的来源，但它们的效用再次取决于对其分化潜力的可预测控制。该项目旨在更好地了解粘附和机械线索如何引导这些干细胞分化成特定的谱系，以便我们可以更好地设计未来的方法来治疗或预防退行性疾病。

DESCRIPTION (provided by applicant): Human mesenchymal stem cells (MSCs) are multipotent stem cells that differentiate into many of the cells resident in musculoskeletal and stromal tissues of the human body, including fibroblasts, chondrocytes, osteoblasts, myocytes, and adipocytes. While differentiation of the MSCs into appropriate lineages may enhance healing of injured tissues, inappropriate lineage specification may be responsible for numerous pathophysiologic processes, including the decreased bone and increased fat in osteoporotic bones, and the calcification of atherosclerotic vessel walls. Regulation of the lineage commitment of MSCs by local microenvironmental cues therefore may be critical to our fundamental understanding of numerous degenerative as well as healing processes. The long term objective of this research is to characterize the cues within the local surrounding microenvironment that drive the lineage specification and differentiation of human mesenchymal stem cells (MSCs), and the molecular pathways involved. The investigator has discovered that adhesion of MSCs to fibronectin regulates a commitment switch in the MSCs between adipogenic and osteogenic lineage specification, through a mechanism involving RhoA signaling and cytoskeletal tension. During the past grant period, he has demonstrated that these adhesive and mechanical cues specifically regulate SMAD and PPARgamma, two key transcription factors critical to osteogenesis and adipogenesis. Specific Aim 1 will be to investigate the how integrin activation regulates BMP-SMAD signaling and osteogenesis. Specific Aim 2 will be to investigate how RhoA regulates SMAD activity. Specific Aim 3 will be to investigate how adhesive and mechanical cues regulate PPARgamma signaling. Together, these studies will define roles of cell adhesion, RhoA, and cytoskeletal tension in MSC lineage commitment, and establish a molecular basis for the regulation of MSC differentiation by microenvironmental cues. PUBLIC HEALTH RELEVANCE: Human mesenchymal stem cells contribute to the maintenance and healing of many musculoskeletal tissues, but they also can produce inappropriate cell lineages to exacerbate disease, such as occurs with calcification of atherosclerotic vessels. They are now being isolated as a promising source of stem cells for regenerative therapies, but again their utility rests upon predictable control of their differentiation potential. This project is designed to develop a better understanding of how adhesive and mechanical cues direct these stem cells to differentiate into specific lineages, such that we may better design future approaches to treat or prevent degenerative diseases.