Mitigating murine acute and chronic Coxsackievirus B3-induced myocarditis with human right atrial appendage-derived stromal cells

We previously have shown the potential of human endomyocardial biopsy (EMB)-derived cardiac adherent proliferating cells (CardAPs) as a new cell-therapeutic treatment option for virus-induced myocarditis. To overcome the limited cell yield per EMB, CardAPs have been isolated from the human right atrial appendage (RAA) in view of allogeneic application and off-the-shelf use. We aimed to investigate the cardioprotective and immunomodulatory potential of RAA-CardAPs in experimental acute and chronic Coxsackievirus B3 (CVB3)-induced myocarditis upon injection in the viral and inflammatory phase. In the acute model, male C57BL6/J mice were intraperitoneally (i.p.) injected with the CVB3 Nancy strain or phosphate buffered saline (PBS). One day after infection, mice were intravenously (i.v.) injected with RAA-CardAPs, EMB-CardAPs (as reference cells) or PBS. For the chronic model, male Naval Medical Research Institute mice were i.p. injected with the CVB3 31-1-93 strain or PBS. Ten days after infection, mice were i.v. injected with RAA-CardAPs. Cardiac function was characterized, followed by harvest of the left ventricle (LV) and spleen for subsequent analysis, 7 and 28 days after CVB3 infection in the acute and chronic model, respectively. In the acute model, RAA-CardAPs decreased cardiac fibrosis and improved cardiac function in CVB3 mice. RAA-CardAPs mice exerted immunomodulatory effects as evidenced by lower LV chemokines expression (C-C motif ligand [CCL]2 and CCL7), CD68+ cells presence, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α, and IL-6 mRNA expression. In the chronic model, RAA-CardAPs reduced cardiac fibrosis and the severity of myocarditis, associated with an improvement in LV function. We conclude that RAA-CardAPs represent a treatment strategy to reduce the development of acute and chronic CVB3-induced myocarditis.