Mechanotransduction in Mesenchymal Stem Cells

人间充质干细胞(MSCs)是形成和修复几乎所有 人体内的机械组织。MSCs现在正从成人中分离出来，以了解 这些细胞是如何作为一个群体进行调控的基础生物学，并探索这些细胞是否可以 被分化并重新植入作为一种细胞疗法，以阻止甚至逆转退化和 对特定组织的损伤。在骨质疏松症等几种疾病过程中，骨质疏松症是 进行性组织退化和损伤可能涉及MSCs主要来源的谱系规格的改变 健康的骨髓间充质干细胞及其子代细胞供应不足。这项研究的长期目标是 是表征粘性和可溶性信号以及下游信号通路的作用，这些信号通路 人骨髓间充质干细胞的谱系鉴定和分化 治疗这些退行性疾病的机制。 间充质干细胞(MSC)是一种多能细胞，能够分化为 结缔组织谱系取决于周围组织微环境中存在的线索。而当 很多工作都集中在鉴定可溶性分化因子上，如骨形态发生蛋白 (BMPS)，细胞与细胞外基质(ECM)的黏附在决定MSC命运中的作用知之甚少。 了解这些线索可能会在许多情况下提供更好的处理方法，专门指导干细胞的命运 包括干细胞治疗。我们最近发现，整合素介导间充质干细胞的黏附 细胞形态和RhoA活性的变化，进而调节MSCs的承诺转换 在成脂和成骨血统之间。本提案背后的工作假设是 这种细胞黏附与来自可溶信号的信号协同调节承诺和分化 这种合作信号涉及RhoA。 因此，这项为期两年的试点和可行性提案的目标是获得更多的初步数据 在三个关键研究中，为了阐述我们的工作假说，然后寻求对此的支持 通过R01机制进行研究。具体目的是：1.研究BMP的协同作用 MSC基因表达中的信号转导与细胞黏附；2.探讨BMP与MSC基因表达的协同作用 信号和细胞黏附在调节RhoA活性中的作用；3.研究BMP和RhoA的作用 在动物模型中对骨髓间充质干细胞承诺的信号。

Human mesenchymal stem cells (MSCs) are the precursor cells that form and heal nearly all of the mechanical tissues in the human body. MSCs are now being isolated from adults to understand the fundamental biology of how these cells are regulated as a population, and to explore whether these cells can be differentiated and re-implanted as a cellular therapy in order to arrest or even reverse degeneration and damage to specific tissues. In several disease processes such as osteoporosis, a major cause of progressive tissue degeneration and damage may involve a shift in lineage specification of the MSCs leading to an inadequate supply of healthy MSCs and their daughter cells. The long term objective of this research is to characterize the role of adhesive and soluble cues, and the downstream signaling pathways, that drive the lineage specification and differentiation of human mesenchymal stem cells, in order to identify novel mechanisms to treat these degenerative diseases. The mesenchymal stem cell (MSC) is a multipotent cell capable of differentiating into distinct connective tissue lineages depending on cues present in the surrounding tissue microenvironment. While much effort has focused on identifying soluble differentiation factors such as the bone morphogenic proteins (BMPs), little is known about the role of cell adhesion to extracellular matrix (ECM) in determining MSC fate. Understanding these cues may provide better handles to specifically direct stem cell fate in many settings involving stem cell therapy. We have recently discovered that integrin-mediated adhesion of MSCs triggers changes in cell morphology and RhoA activity, which in turn modulate a commitment switch in MSCs between adipogenic and osteogenic lineages. The working hypothesis underlying the present proposal is that cell adhesion cooperates with signals from soluble cues to regulate the commitment and differentiation of human mesenchymal stem cells, and that this cooperative signaling involves RhoA. The goal of this 2-year Pilot and Feasibility proposal therefore is to obtain additional preliminary data in three key studies in order to elaborate our working hypothesis, and then to pursue support for this research by the R01 mechanism. The specific aims are: 1. To investigate the cooperative role of BMP signaling and cell adhesion in MSC gene expression; 2. To investigate the cooperation between BMP signaling and cell adhesion in regulating RhoA activity; and 3. To investigate the effects of BMP and RhoA signaling on MSC commitment in an animal model.