Characterization of key mechanisms involved in transmigration and invasion of mesenchymal stem cells

Stem cell therapy using human adult mesenchymal stem cells (MSCs) has emerged as a novel strategy for the treatment of a variety of damaged tissues. For a successful systemic stem cell therapy MSCs have to exit the blood circulation by transmigrating across the endothelium and invading into the target tissue. Elevating our knowledge on these core processes might help to optimize stem cell based therapies. The first part of the present study provides insights into key mechanisms involved in the transmigration and invasion of MSCs. Different model systems as well as in vivo studies revealed that MSCs quickly come into contact with the endothelium and subsequently exit the blood circulation by (1) integrating into the endothelium, (2) transmigrating across the endothelial barrier via the insertion of plasmic podia, (3) penetrating the basement membrane and subsequently invading the surrounding tissue. Additionally, it was proven that transmigration of human MSCs not only requires the interaction of very late antigen-4 (VLA-4) and its most important ligand vascular cell adhesion molecule-1 (VCAM-1), but also triggers a clustering of beta 1 integrins. Furthermore, upon invading into cardiac tissue MSCs secrete active matrix metalloproteinase (MMP)-2, but not MMP-9. This study also demonstrates that both the time course and the morphological aspects of MSC transmigration differ depending on the endothelial phenotype, thus indicating, that a variable capacity for transendothelial migration exists within the vasculature. Furthermore, addition of cytokines, mainly vascular endothelial growth factor (VEGF) and erythropoietin (EPO), accelerate the transmigration of MSCs at early stages. Moreover, nitric oxide (NO) and reactive oxygen species (ROS) are released by MSCs upon contact with endothelial cells; manipulating the NO and ROS system by donors and inhibitors resulted in alterations of the transmigratory capacity of MSCs. The second part of the study deals with two possible strategies to enhance the transmigration of MSCs and thereby their therapeutic effectiveness. First, the results demonstrate that genetic modification of MSCs using adenoviral overexpression of the chemokine receptor CXCR4 does not lead to an increase in the transmigration efficiency. Second, focussed pretreatment of the endothelium by a novel and non-invasive technique using ultrasound-mediated microbubble stimulation (UMS) induces a targeted improvement of MSC attraction, transmigration and invasion into non-ischemic as well as into ischemic myocardium. This effect was most likely due to the release of nitric oxide, cytokines and the regional activation of proteases. Thus, UMS represents a forward-looking possibility to increase the efficiency of MSC engraftment by modulating the process of transmigration in a targeted and non-invasive manner