Combined Effects of Nanofiber Matrix Elasticity and VEGF-A on the Differentiation of Mesenchymal Stem Cells Towards Mature Endothelial Cells

The potential of mesenchymal stem cell (MSC) in the treatment of vascular diseases is becoming increasingly recognized.[1] The use of MSC to produce a functional endothelium in synthetic vascular grafts is of particular interest as this would prevent common graft failures such as neointima hyperplasia and thrombus. Current attempts to produce a functional endothelial layer with endothelial cells (EC) have limited success due to the need for invasive surgery and the limited expansion capability these cells have in vitro.[2] MSC are a powerful cellular alternative as they are easily obtained through a bone marrow biopsy, have a large expansion capability in vitro, are multipotent, and thromboresistant. Individual factors such as matrix elasticity, matrix structure, growth factors, and mechanical stimulations have all been shown to contribute to MSC differentiation towards vascular phenotypes in vivo. However, the response of MSCs to the combined effects of these factors is not well characterized. Additionally, many experiments studying MSC differentiation are conducted on 2D substrates instead of simulating the 3D nanofiber matrix structure found in-vivo. Furthermore, little is known about the underlying cell signaling pathways that direct vascular differentiation. Currently, researchers have yet to achieve MSC differentiation into mature, functional endothelial cells, a critical step for regenerating healthy vascular tissue. We hypothesize that the combined effects of VEGF-A growth factor and a 3D matrix elasticity that mimicking the mechanochemical properties of in-vivo intima induce more complete MSC differentiation into EC expressing mature markers through the regulation of critical vascular signaling molecules such as MAPK/ERK and RhoA/Rock.