A Small-Molecule Screen for Enhanced Homing of Systemically Infused Cells

Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies. [Display omitted] •Compounds were screened to maximize MSC surface expression of ICAM-1-binding ligands•Ro-31-8425, a kinase inhibitor, was identified to enhance cell adhesion under flow•Preconditioning of MSCs enabled their targeting to a distant inflamed tissue•Improved therapeutic anti-inflammatory response was also achieved Levy et al. developed a multi-step screening process to identify small molecules that improve targeting of systemically infused mesenchymal stem cells to sites of inflammation, resulting in a heightened anti-inflammatory response. This multi-step screening platform may significantly improve clinical outcomes of cell-based therapies.