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MSC分化成适当的谱系可以促进损伤组织的愈合，但不适当的谱系特异性可能导致许多病理生理过程，包括骨质疏松骨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，通过局部微环境线索调节MSC的谱系承诺可能对我们对许多退行性疾病以及愈合过程的基本理解至关重要。本研究的长期目标是表征驱动人类间充质干细胞（MSC）谱系特化和分化的局部周围微环境中的线索，以及所涉及的分子途径。研究者已经发现，MSC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MSC在成脂和成骨谱系特化之间的定向转换。在过去的资助期间，他已经证明，这些粘附和机械线索专门调节SMAD和PPARgamma，这两个关键转录因子对骨生成和脂肪生成至关重要。具体目标1将研究整合素活化如何调节BMP-SMAD信号传导和骨生成。具体目标2将是研究RhoA如何调节SMAD活性。具体目标3将是研究如何粘合剂和机械线索调节PPARgamma信号。总之，这些研究将确定细胞粘附，RhoA和细胞骨架张力在MSC谱系定型中的作用，并建立微环境因子调控MSC分化的分子基础。 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持和愈合，但它们也可以产生不适当的细胞谱系以加剧疾病，例如动脉粥样硬化血管的钙化。它们现在被分离为再生疗法的干细胞的有希望的来源，但它们的效用再次依赖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.