Enhanced migration of bone marrow-derived cells mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy

Abstract

Aims: Endogenous circulation of bone marrow-derived cells (BMCs) was observed in patients with dilated cardiomyopathy (DCM) who showed cardiac upregulation of Vascular Cell Adhesion Protein-1 (VCAM-1). However, the underlying pathophysiology is currently unknown. Thus, we aimed to analyze circulation, homing and G-CSF based mobilization of BMCs in a murine model of virus-induced DCM. Methods and results: Mice with coxsackievirus B3 (CVB3) induced DCM and healthy controls were analyzed regarding their myocardial homing factors by PCR. To determine cardiac VCAM-1 expression ELISA and immunohistochemistry was applied. Flow cytometry was performed to analyze BMCs and resident cardiac stem cells (CSCs). Heart function was evaluated by cardiac MRI before and 4 weeks after G-CSF treatment. In murine CVB3-induced DCM an increase of BMCs in peripheral blood and a decrease of BMCs in bone marrow was observed. We found an enhanced migration of Very Late Antigen-4 (VLA-4+) BMCs to the diseased heart overexpressing VCAM-1 and higher numbers of CSCs. Mobilization of BMCs by G-CSF boosted homing via VCAM-1/VLA-4 interaction and reduced apoptotic cardiomyocytes. Significant improvement of cardiac function was detected by MRI in G-CSF treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF dependent effects on stem cell homing and CSC proliferation. Conclusion: This is the first study showing that in virus-induced DCM VCAM-1/VLA-4 interaction is crucial for recruitment of circulating BMCs leading to a proliferation of CSCs and to beneficial antiapoptotic effects resulting in improved cardiac function after G-CSF induced mobilization.