Stem cell therapies offer enormous hope for solving some of the most tragic illnesses, diseases, and tissue defects world-wide. Mesenchymal stem cells (MSCs), also referred to as connective tissue progenitor cells have immediate clinical utility for treatment of numerous ailments including heart disease due to their convenient isolation, lack of significant immunogenicity, ease of transfection for ex-vivo modification, lack of ethical controversy, and their potential to differentiate into cardiac myocytes. However, a significant barrier to the effective implementation of cell therapies is the inability to target these cells with high efficiency to tissues of interest. This research will build on published and unpublished results generated by the PI and Co-PI (who have been working together during the past 2 years).
The specific aims detailed herein are designed to address the hypothesis that mesenchymal stem cells that are engineered to roll and firmly adhere to vascular endothelim will undergo transmigration. The project will consist of three specific aims. We will assess the ability of MSCs engineered with rolling ligands to firmly adhere to 2D surfaces coated with cell adhesion molecules and we will assess the impact of the cell surface modification on the expression of relevant homing receptors (Aim 1). We will also examine the ability of the modified MSCs to firmly adhere and transmigrate through monolayers of activated endothelial cells (AIM 2). In addition to examining firm adhesion and transmigration under static conditions, and to better mimic the in vivo environment, we will analyze the ability of modified MSCs to firmly adhere and transmigrate under shear stress conditions (Aim 3). It is important to validate our hypothesis in vitro prior to testing the trafficking potential of chemically engineered MSCs in vivo which we hope to explore in a future RO1 proposal. This in vitro work would also help us further establish a suitable in vitro model for interrogating cell trafficking behavior.
In this project we will incorporate adhesion ligands that promote cell rolling, onto the surface of culture expanded mesenchymal stem cells to enhance firm adhesion and transendothelial migration on endothelial monolayers. We will also develop an in vitro model to examine interactions with endothelial cell monolayers that are pre-conditioned under shear stress conditions.
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