Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy.
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.
Medical Department I, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany, Stefan.Brunner@med.uni-muenchen.de.
Stefan
S
Brunner
Hans D
HD
Theiss
Monika
M
Leiss
Ulrich
U
Grabmaier
Johanna
J
Grabmeier
Bruno
B
Huber
Markus
M
Vallaster
Dirk Andre
DA
Clevert
Martina
M
Sauter
Reinhard
R
Kandolf
Christian
C
Rimmbach
Robert
R
David
Karin
K
Klingel
Wolfgang-Michael
WM
Franz
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D002465:Cell Movement / Q000502:physiology*; D003384:Coxsackievirus Infections; D004195:Disease Models, Animal; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor