Suppression of T cells by mesenchymal and cardiac progenitor cells is partly mediated via extracellular vesicles.

Adverse remodeling after myocardial infarction (MI) is strongly influenced by T cells. Stem cell therapy after MI, using mesenchymal stem cells (MSC) or cardiomyocyte progenitor cells (CMPC), improved cardiac function, despite low cell retention and limited differentiation. As MSC secrete many factors affecting T cell proliferation and function, we hypothesized the immune response could be affected as one of the targets of stem cell therapy. Therefore, we studied the immunosuppressive properties of human BM-MSC and CMPC and their extracellular vesicles (EVs) in co-culture with activated T cells. Proliferation of T cells, measured by carboxyfluorescein succinimidyl ester dilution, was significantly reduced in the presence of BM-MSC and CMPC. The inflammatory cytokine panel of the T cells in co-culture, measured by Luminex assay, changed, with strong downregulation of IFN-gamma and TNF-alpha. The effect on proliferation was observed in both direct cell contact and transwell co-culture systems. Transfer of conditioned medium to unrelated T cells abrogated proliferation in these cells. EVs isolated from the conditioned medium of BM-MSC and CMPC prevented T cell proliferation in a dose-dependent fashion. Progenitor cells presence induces up- and downregulation of multiple previously unreported pathways in T cells. In conclusion, both BM-MSC and CMPC have a strong capacity for in vitro immunosuppression. This effect is mediated by paracrine factors, such as extracellular vesicles. Besides proliferation, many additional pathways are influenced by both BM-MSC and CMPC.

Heart Failure in Chronic Myocarditis: A Role for microRNAs?

Myocarditis is an inflammatory disease of the heart, which can persist over a long time. During this time, known as the chronic phase of myocarditis, ongoing inflammation damages the cardiomyocytes. The loss of cardiac cells culminates in the development of dilated cardiomyopathy, often followed by non-ischemic heart failure due to diminished cardiac function. During the course of the disease, expression levels of non-coding small RNAs, called microRNAs (miRNAs), change. Although mainly studied in the acute setting, some of these changes in expression level appear to persist in the chronic phase. In addition to being a much-needed diagnostic tool, these miRNA could provide new treatment options. miRNA-based intervention strategies already showed promising results in the treatment of ischemic cardiovascular diseases in preclinical animal models. By implementing more knowledge on the role of miRNAs in the progression towards heart failure, this can potentially be used in the development of miRNA-based therapeutic interventions in the treatment of myocarditis and thereby preventing the progression towards heart failure. The first part of this review will focus on the natural course of myocarditis and the progression towards heart failure. Secondly, we will discuss the current knowledge on alterations of miRNA expression patterns, and suggest some possible future interventions.

Circulating microRNAs as novel biomarkers for the early diagnosis of acute coronary syndrome.

Small non-coding microRNAs (miRNAs) are important physiological regulators of post-transcriptional gene expression. miRNAs not only reside in the cytoplasm but are also stably present in several extracellular compartments, including the circulation. For that reason, miRNAs are proposed as diagnostic biomarkers for various diseases. Early diagnosis of acute coronary syndrome (ACS), especially non-ST elevated myocardial infarction and unstable angina pectoris, is essential for optimal treatment outcome, and due to the ongoing need for additional identifiers, miRNAs are of special interest as biomarkers for ACS. This review highlights the nature and cellular release mechanisms of circulating miRNAs and therefore their potential role in the diagnosis of myocardial infarction. We will give an update of clinical studies addressing the role of circulating miRNA expression after myocardial infarction and explore the diagnostic value of this potential biomarker.

Cardiac stem cell therapy to modulate inflammation upon myocardial infarction.

BACKGROUND: After myocardial infarction (MI) a local inflammatory reaction clears the damaged myocardium from dead cells and matrix debris at the onset of scar formation. The intensity and duration of this inflammatory reaction are intimately linked to post-infarct remodeling and cardiac dysfunction. Strikingly, treatment with standard anti-inflammatory drugs worsens clinical outcome, suggesting a dual role of inflammation in the cardiac response to injury. Cardiac stem cell therapy with different stem or progenitor cells, e.g. mesenchymal stem cells (MSC), was recently found to have beneficial effects, mostly related to paracrine actions. One of the suggested paracrine effects of cell therapy is modulation of the immune system. SCOPE OF REVIEW: MSC are reported to interact with several cells of the immune system and could therefore be an excellent means to reduce detrimental inflammatory reactions and promote the switch to the healing phase upon cardiac injury. This review focuses on the potential use of MSC therapy for post-MI inflammation. To understand the effects MSC might have on the post-MI heart the cellular and molecular changes in the myocardium after MI need to be understood. MAJOR CONCLUSIONS: By studying the general pathways involved in immunomodulation, and examining the interactions with cell types important for post-MI inflammation, it becomes clear that MSC treatment might provide a new therapeutic opportunity to improve cardiac outcome after acute injury. GENERAL SIGNIFICANCE: Using stem cells to target the post-MI inflammation is a novel therapy which could have considerable clinical implications. This article is part of a Special Issue entitled Biochemistry of Stem Cells.