Mechanotransduction in Mesenchymal Stem Cells

点击翻译按钮获取中文摘要

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.