Using bacterial adhesins to direct human stem cells to the myocardium

The efficient delivery and adherence of cells to a site of interest, a process termed “homing”, remains an elusive goal for cell therapies. Intravenous or intra-arterial infusion of cells inevitably leads to the undesired and detrimental accumulation of the cells at the lungs and liver, which reduces the efficiency of systemic delivery and increases the likelihood of producing lethal microemboli.

We have developed a new methodology involving the introduction of exogenous proteins directly anchored to the cell membrane in order to modulate cell behaviour and achieve targeted homing. In this work, we showed that a designer protein-surfactant hybrid construct with inherent cardiac tissue homing properties can be rationally engineered to spontaneously insert into the plasma membrane of human mesenchymal stem cells (hMSCs). This was achieved by hijacking the in-built ability of Streptococcus gordonii to home to cardiac tissue by displaying multiple copies of the fibronectin binding domain of the bacterial adhesion protein (bap) on the surface of hMSCs. In order to anchor the construct to the membrane, the bap was fused to supercharged GFP (scGFP), which was then conjugated to surfactant molecules displaying membrane binding properties. The results shown in this work demonstrate that the construct maintains the dual biophysical properties of bap and scGFP, and associates with hMSC membrane with no visual changes in cell morphology. Significantly, the construct is not cytotoxic, does not ellicit an immune response in mice, and directs hMSCs delivered either intracardially or intravenously to the myocardium, without a concomitant increase in the lungs. This cell membrane display system is completely independent of cell type and can therefore be readily applied to other cell types using a wide array of protein-based targeting molecules.