Mesenchymal Stem Cells and the Microenvironment

描述(申请人提供)：人骨髓间充质干细胞(MSCs)是一种多能干细胞，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。尽管将MSCs分化为合适的谱系可能会促进损伤组织的愈合，但不适当的谱系规格可能是导致许多病理生理过程的原因，包括骨质疏松骨骼中的骨减少和脂肪增加，以及动脉粥样硬化血管壁的钙化。因此，通过局部微环境信号调节MSCs的谱系承诺对于我们对许多退化和修复过程的基本理解可能是至关重要的。这项研究的长期目标是表征局部周围微环境中驱动人间充质干细胞(MSCs)谱系指定和分化的线索，以及涉及的分子途径。研究人员发现，MSCs与纤维连接蛋白的黏附通过涉及RhoA信号和细胞骨架张力的机制，调节MSCs在成脂和成骨谱系之间的承诺转换。在过去的授予期间，他证明了这些黏附和机械信号专门调节SMAD和PPARGamma，这两个关键转录因子对成骨和脂肪生成至关重要。具体目标1将是研究整合素激活如何调节BMP-SMAD信号和成骨。具体目标2将是调查RhoA如何调节SMAD活动。具体目标3将是研究粘合剂和机械信号如何调节PPARGamma信号。总之，这些研究将确定细胞黏附、RhoA和细胞骨架张力在MSC谱系承诺中的作用，并为微环境线索调控MSC分化奠定分子基础。 公共卫生相关性：人类间充质干细胞有助于许多肌肉骨骼组织的维护和愈合，但它们也可以产生不适当的细胞谱系来加重疾病，例如动脉粥样硬化血管的钙化。它们现在被分离出来，作为再生治疗的一种有希望的干细胞来源，但它们的用途再次取决于对其分化潜力的可预测控制。这个项目旨在更好地理解粘附性和机械性线索如何引导这些干细胞分化为特定的谱系，以便我们可以更好地设计未来治疗或预防退行性疾病的方法。

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.