Cell therapy - showing cells the way home

The clinical potential of cell-based therapies is limited by poor targeting of systemically infused cells to diseased tissues [1]. In our recent study, we have developed a multi-step screening platform to identify small molecules that boost the homing properties of mesenchymal stem cells (MSCs) to sites of inflammation [2]. First, a medium-throughput screen was designed to identify small molecules that upregulate surface expression of the homing integrin, cd11a (integrin αL). Ro-31-8425, a kinase inhibitor, was identified as the most potent inducer of cd11a surface expression, and was also shown to significantly increase MSC firm adhesion to the endothelial ligand of cd11a, ICAM-1, using a microfluidics-based firm adhesion assay [3]. Finally, systemically infused Ro-31-8425-pretreated MSCs displayed improved homing to sites of inflammation and a superior anti-inflammatory impact in a murine ear inflammation model. Using small molecule pretreatment to control cell behavior post-infusion possesses multiple advantages over other bioengineering approaches, such as chemical surface modification or DNA engineering. Small molecule-induced transient modification of signaling pathways offers a potentially safe, simple, cost-effective and highly scalable approach. Moreover, the described versatile multi-step screening platform can be readily tweaked to potentially target virtually any cell type to multiple sites in the body. This platform consists of four essential steps: i) Screening small molecule libraries to identify compounds that induce expression of molecules of interest; ii) Functional validation of hits from the first step to assess the corresponding functional properties of pretreated cells; iii) In-vivo functional validation step to evaluate the function of pretreated cells in the suitable disease model; iv) Assessing therapeutic efficacy following infusion of pretreated cells. This platform can be customized by modifying the first screening step to identify small molecule inducers of other disease-specific homing ligands/chemokine receptors and by altering the in-vitro functional step to assess homing properties corresponding to a key step in the cell homing cascade (i.e., rolling, chemokine-directed migration and firm adhesion) [4]. Secretion of chemokines and expression of homing receptors on the endothelium of multiple tissues during disease onset can both be used for targeting [4]. For instance, inducing expression of CXCR1, Mac-1 and CXCR4 may target infused cells specifically to sites of myocardial infarction, expression of CXCR3 and LFA-1 may shuttle cells to the diseased brain in multiple sclerosis patients and expression of CCR9 and α4β7 may direct cells to the inflamed intestine characteristic of Crohn's disease [4]. Tailoring the steps of this platform to target disease-specific …