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Published on: July 10, 2019
Human cardiac-derived adherent proliferating cells reduce murine acute Coxsackievirus B3-induced myocarditis
Kapka Miteva1, Marion Haag, Jun Peng
1Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Berlin, Germany.
Insights
Cardiac-derived adherent proliferating cells (CAPs) show promise in treating Coxsackievirus B3-induced myocarditis. These novel cells reduce viral load, cardiac apoptosis, and improve heart function, offering a new therapeutic strategy for inflammatory cardiomyopathy.
Area of Science:
- Cardiology
- Immunology
- Cell Biology
Background:
- Inflammatory cardiomyopathy, often caused by Coxsackievirus B3 (CVB3), has a poor prognosis with conventional therapy.
- Novel cardiac-derived adherent proliferating cells (CAPs) possess mesenchymal stromal cell-like properties, including anti-apoptotic and immunomodulatory effects.
- Investigating CAPs as a therapeutic strategy for acute CVB3-induced myocarditis is warranted.
Purpose of the Study:
- To assess the therapeutic potential of CAPs in an acute CVB3-induced myocarditis model.
- To evaluate the safety and efficacy of CAPs in reducing viral load and cardiac damage.
Main Methods:
- Assessed CAPs' susceptibility to CVB3 infection by analyzing coxsackie- and adenovirus receptor (CAR) and CD55 expression.
- Co-cultured CAPs with CVB3-infected cardiomyocytes to evaluate effects on apoptosis and viral release.
- Administered CAPs to a murine model of CVB3 myocarditis and assessed cardiac function, viral load, apoptosis, and immune cell responses.
Main Results:
- CAPs exhibited minimal CVB3 infectivity, significantly reducing viral copy numbers and particle release.
- CAPs mitigated CVB3-induced cardiomyocyte apoptosis and viral progeny in vitro.
- In vivo, CAPs decreased cardiac apoptosis and viral load, improved left ventricular contractility, and modulated immune cell activity, including increased regulatory T cells.
Conclusions:
- CAPs are a distinct cell type with significant therapeutic potential for acute CVB3-induced myocarditis.
- CAPs demonstrate immunomodulatory and anti-apoptotic effects, mediated by nitric oxide, IL-10, and interferon-γ.
- CAPs represent a promising novel cell-based therapy for inflammatory cardiomyopathy.
Background:
Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis.
Methodology/Principal Findings:
To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression.
Conclusions:
We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis.
