Abstract 13214: A Small Molecule Integrin Agonist Enhances Progenitor Cell Adhesion to Key Homing Receptors for Regenerative Therapy
Adult stem cell therapy has shown promise in clinical trials toward improved functional outcomes following myocardial infarction. An obstacle that has slowed the development of such therapies is the low retention and engraftment rate at the site of injury following local delivery of cells. One approach to increase retention rates is the induction of stronger interactions between surface adhesion molecules on stem/progenitor cells and their counter-receptors expressed by heart tissue and the surrounding matrix. To this end, we describe here for the first time a non-peptidic, small molecule integrin agonist that promotes adhesion of VLA-4 (integrin α4β1) expressing cells to two ligands: vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 variant of fibronectin. In vitro static adhesion assays using cultured cell lines show the compound THI0019 dramatically increases the number of cells bound to VCAM-1 or CS-1 by one to two orders of magnitude with an EC50 of 4.8 ± 0.3 uM. Similar results were obtained using bone marrow derived Flk-1+ Tie-2+ endothelial progenitor cells (EPC) expressing VLA−4. Previous modeling studies and published crystal structures of related integrin subunits predict that THI0019 exerts its effects primarily through the α4 subunit of VLA−4. This hypothesis is supported by data showing that the compound does not induce the expression of an activation dependent epitope recognized by a mAb to the β1 subunit, yet shows synergistic effects on cell adhesion when used in combination with this same β1 antibody. Importantly, the compound does not induce homotypic cellular aggregation which is a favorable result considering the clinical implications. Because many progenitor cell types under evaluation in the clinic express high levels of VLA-4, including EPC and hematopoietic progenitor cells, THI0019 may prove to be a useful adjunct to present stem cell therapies.
- © 2010 by American Heart Association, Inc.