Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy

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.

Attenuation of cardiac hypertrophy by G‐CSF is associated with enhanced migration of bone marrow‐derived cells

“…Recently, Brunner et al . were able to demonstrate in a murine model of virus‐induced DCM that G‐CSF‐induced VCAM‐1/VLA‐4 interaction is crucial for the recruitment of circulating BMCs to the myocardium . Notably, they could not detect increased numbers of c‐kit + or enhanced expression of SCF, suggesting a different regulation of cytokine profiles after DCM and pressure‐induced LV hypertrophy.…”

Advanced Age Impairs Cardioprotective Function of Mesenchymal Stem Cell Transplantation from Patients to Myocardially Infarcted Rats

“…Many factors may impair the effect of MSC therapy, such as diabetes [23], myocarditis [20] and antineoplastic drug treatment [21]. Thus, advanced age is only one risk factor [24].…”

“…The histochemical detection of apoptotic cells was performed as previously reported [20]. The tissue blocks were fixed in 4% paraformaldehyde and incubated with proteinase K. Fragments of DNA in the tissue sections were analyzed using a TUNEL detection kit (Promega).…”

Increased Mobilization of CD45+CD34+VLA-4+ Cells in Acute Viral Myocarditis Induced by Coxsackievirus B3

“…Koch et al [23] demonstrated that MSCs home to infracted heart tissue via the VCAM-1/VLA-4 axis. The VCAM-1/VLA-4 interrelationship is crucial for increasing the migration of BMCs into the injured myocardium [24]. Our study demonstrated a higher VCAM-1 expression in acute VCM heart than in healthy control mice followed by increased neovascularization around inflammatory cells.…”

“…The migration of VLA-4+ cells is facilitated by upregulation of VCAM-1 expression within diseased hearts. In addition, VCAM-1 expression is significantly increased in virus-positive DCM hearts and upregulated in acute and chronic myocarditis [9]. Inflammation plays a pivotal role in the mobilization of BMCs to the heart and differentiation into myocardial cells [10].…”