1. Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy
- Author
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Johanna Grabmeier, Hans D. Theiss, Martina Sauter, Stefan Brunner, Monika Leiss, Christian Rimmbach, Robert David, Bruno C. Huber, Ulrich Grabmaier, Wolfgang-Michael Franz, Reinhard Kandolf, Dirk-André Clevert, Markus Vallaster, and Karin Klingel
- Subjects
Cardiac function curve ,Cardiomyopathy, Dilated ,Pathology ,medicine.medical_specialty ,Physiology ,Cardiomyopathy ,Coxsackievirus Infections ,Vascular Cell Adhesion Molecule-1 ,Bone Marrow Cells ,Enzyme-Linked Immunosorbent Assay ,Biology ,Integrin alpha4beta1 ,Real-Time Polymerase Chain Reaction ,Flow cytometry ,chemistry.chemical_compound ,Mice ,Downregulation and upregulation ,Cell Movement ,Physiology (medical) ,Granulocyte Colony-Stimulating Factor ,medicine ,Animals ,Humans ,VCAM-1 ,medicine.diagnostic_test ,Stem Cells ,Dilated cardiomyopathy ,medicine.disease ,Flow Cytometry ,Immunohistochemistry ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Echocardiography ,Immunology ,cardiovascular system ,Bone marrow ,Stem cell ,Cardiology and Cardiovascular Medicine - Abstract
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, migration and G-CSF-based mobilization of BMCs in a murine model of virus-induced DCM. 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 were applied. Flow cytometry was performed to analyze BMCs. Cardiac diameters and function were evaluated by echocardiography 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 CD45⁻CD34⁻Sca-1⁺ and CD45⁻CD34⁻c-kit⁺ cells. Mobilization of BMCs by G-CSF boosted migration along the VCAM-1/VLA-4 axis and reduced apoptosis of cardiomyocytes. Significant improvement of cardiac function was detected by echocardiography in G-CSF-treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF-dependent effects on stem cell migration and cardiac function. 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 beneficial anti-apoptotic effects resulting in improved cardiac function after G-CSF-induced mobilization.
- Published
- 2013