Human mesenchymal stem cells (MSCs) are the precursor cells that form and heal nearly all of themechanical tissues in the human body. MSCs are now being isolated from adults to understand thefundamental biology of how these cells are regulated as a population, and to explore whether these cells canbe differentiated and re-implanted as a cellular therapy in order to arrest or even reverse degeneration anddamage to specific tissues. In several disease processes such as osteoporosis, a major cause ofprogressive tissue degeneration and damage may involve a shift in lineage specification of the MSCs leadingto an inadequate supply of healthy MSCs and their daughter cells. The long term objective of this researchis to characterize the role of adhesive and soluble cues, and the downstream signaling pathways, that drivethe lineage specification and differentiation of human mesenchymal stem cells, in order to identify novelmechanisms to treat these degenerative diseases.The mesenchymal stem cell (MSC) is a multipotent cell capable of differentiating into distinctconnective tissue lineages depending on cues present in the surrounding tissue microenvironment. Whilemuch 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 settingsinvolving stem cell therapy. We have recently discovered that integrin-mediated adhesion of MSCs triggerschanges in cell morphology and RhoA activity, which in turn modulate a commitment switch in MSCsbetween adipogenic and osteogenic lineages. The working hypothesis underlying the present proposal isthat cell adhesion cooperates with signals from soluble cues to regulate the commitment and differentiationof 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 datain three key studies in order to elaborate our working hypothesis, and then to pursue support for thisresearch by the R01 mechanism.
The specific aims are: 1. To investigate the cooperative role of BMPsignaling and cell adhesion in MSC gene expression; 2. To investigate the cooperation between BMPsignaling and cell adhesion in regulating RhoA activity; and 3. To investigate the effects of BMP and RhoAsignaling on MSC commitment in an animal model.
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