Bone marrow mesenchymal stem cells (BMMSCs) are expandable in vitro, have little immunogenic response upon transplantation and can differentiate into different cell types, including smooth muscle cells (SMC). Thus, BMMSCs have tremendous potential as a cell source for vascular repair and the fabrication of tissue engineered vascular grafts. However, the regulation of BMMSC differentiation by vascular microenvironment remains to be determined. The cyclic uniaxial mechanical strain (the circumferential component of hemodynamic force applied on blood vessel wall) and transforming growth factor beta (TGF-beta) play important roles in vascular remodeling. The Principal Investigator (PI) proposes that specific vascular mechanical and chemical factors (e.g., TGF-beta) may promote BMMSC differentiation into SMC. Based on the preliminary studies, The PI hypothesizes that: (1) cyclic, uniaxial mechanical strain increases the expression of smooth muscle contractile markers (SMCMs) in BMMSCs, which is mediated by CArG element--a common cis-element in the promoter of SMCM genes, (2) small GTPase Rho functions as a molecular switch for the regulation of CArG element activity in BMMSCs in response to cyclic uniaxial strain, and (3) TGF-beta regulates Kruppel-like factor 4 (KLF4) expression, and cooperates with mechanical strain to induce the expression of myocardin--a transcription co-factor critical for SMC differentiation, thus synergizing with mechanical strain induced SMCM expression.
Three Specific Aims are proposed to test the three hypotheses respectively: (1) To determine the effects of cyclic uniaxial strain on the genetic re-programming in BMMSCs, and to determine the role of CArG element in strain-induced SMCM expression; (2) To determine the roles of Rho-mediated signaling in the regulation of CArG element activity in BMMSCs in response to cyclic uniaxial strain; (3) To investigate the effects of TGF-beta on the expression of myocardin, KLF4 and SMCMs in the absence and presence of mechanical strain. A multidisciplinary approach will be used to test the hypothesis. To mimic in vivo condition, BMMSCs will be cultured on micropatterned elastic membranes to keep the cells align in the strain direction. The genetic re-programming of BMMSCs will be analyzed by using DNA microarrays. The roles of signaling molecules, transcription factors and cis-elements will be determined by using respective mutants and inhibitors. The results of this study will advance the understanding of mechanotransduction in stem cell differentiation, and provide a rational basis for controlling BMMSC differentiation in vitro for vascular tissue engineering applications, e.g., using BMMSC-derived SMCs to construct tissue-engineered vascular grafts.
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