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Published on: July 10, 2019
Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated
Stefan Brunner1, Hans D Theiss, Monika Leiss
1Medical Department I, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany, Stefan.Brunner@med.uni-muenchen.de.
Insights
In virus-induced dilated cardiomyopathy (DCM), bone marrow-derived cells (BMCs) migrate to the heart via the VCAM-1/VLA-4 pathway. Granulocyte-colony stimulating factor (G-CSF) enhances this migration, improving cardiac function and reducing cell death.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Immunology
Background:
- Dilated cardiomyopathy (DCM) involves endogenous bone marrow-derived cells (BMCs) circulation, linked to cardiac Vascular Cell Adhesion Protein-1 (VCAM-1) upregulation.
- The precise mechanism of BMCs' role and mobilization in DCM pathophysiology remains unclear.
Purpose of the Study:
- To investigate the circulation, migration, and Granulocyte-colony stimulating factor (G-CSF)-mediated mobilization of BMCs in a murine model of virus-induced DCM.
- To elucidate the role of the VCAM-1/VLA-4 axis in BMCs recruitment and its impact on cardiac function.
Main Methods:
- Established a coxsackievirus B3 (CVB3)-induced DCM model in mice, analyzing myocardial homing factors via PCR.
- Assessed cardiac VCAM-1 expression using ELISA and immunohistochemistry; analyzed BMCs via flow cytometry.
- Evaluated cardiac function and diameters by echocardiography before and after G-CSF treatment, including VCAM-1 blockade experiments.
Main Results:
- Virus-induced DCM mice exhibited increased peripheral blood BMCs and decreased bone marrow BMCs.
- Enhanced migration of Very Late Antigen-4 (VLA-4⁺) BMCs to VCAM-1-overexpressing hearts was observed, along with increased specific stem cell populations.
- G-CSF treatment boosted BMC migration via the VCAM-1/VLA-4 pathway, reduced cardiomyocyte apoptosis, and significantly improved cardiac function.
- VCAM-1 blockade diminished G-CSF's effects on stem cell migration and cardiac recovery.
Conclusions:
- The VCAM-1/VLA-4 interaction is critical for recruiting circulating BMCs to the heart in virus-induced DCM.
- G-CSF-induced BMC mobilization promotes beneficial anti-apoptotic effects and improves cardiac function in DCM.
- Targeting the VCAM-1/VLA-4 pathway offers a potential therapeutic strategy for virus-induced DCM.
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.
