Cardiomyocyte Transplantation after Myocardial Infarction Alters the Immune Response in the Heart.

Robert David,Tobias Lindner,Markus Wolfien,Hermann Lang,Praveen Vasudevan,Heiko Lemcke,Ralf Gaebel,Anna Skorska,Robby Engelmann,Dirk Koczan,Gustav Steinhoff,Cajetan Immanuel Lang,Olaf Wolkenhauer,Bernd Joachim Krause,Brigitte Vollmar

doi:10.3390/cells9081825

Robert David, Tobias Lindner + Show 13 more

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https://doi.org/10.3390/cells9081825

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Journal: Cells	Publication Date: Aug 3, 2020
Citations: 13	License type: CC BY 4.0

Affiliation: University of Rostock, Stellenbosch University

Abstract

We investigated the influence of syngeneic cardiomyocyte transplantation after myocardial infarction (MI) on the immune response and cardiac function. Methods and Results: We show for the first time that the immune response is altered as a result of syngeneic neonatal cardiomyocyte transplantation after MI leading to improved cardiac pump function as observed by magnetic resonance imaging in C57BL/6J mice. Interestingly, there was no improvement in the capillary density as well as infarct area as observed by CD31 and Sirius Red staining, respectively. Flow cytometric analysis revealed a significantly different response of monocyte-derived macrophages and regulatory T cells after cell transplantation. Interestingly, the inhibition of monocyte infiltration accompanied by cardiomyocyte transplantation diminished the positive effect of cell transplantation alone. The number of CD68+ macrophages in the remote area of the heart observed after four weeks was also different between the groups. Transcriptome analysis showed several changes in the gene expression involving circadian regulation, mitochondrial metabolism and immune responses after cardiomyocyte transplantation. Conclusion: Our work shows that cardiomyocyte transplantation alters the immune response after myocardial infarction with the recruited monocytes playing a role in the beneficial effect of cell transplantation. It also paves the way for further optimization of the efficacy of cardiomyocyte transplantation and their successful translation in the clinic.

Highlights

Cardiovascular diseases are a major cause of morbidity and mortality in the world [1]
Three days after myocardial infarction (MI), either 1 × 106 neonatal GFP cardiomyocytes suspended in 15 μL MatrigelTM (MIC) or only MatrigelTM (MI) were injected intramyocardially
We observed a significant decrease in the percentage of monocyte-derived macrophages (Figure 2B) in the heart, with a corresponding decrease in the contribution of monocyte-derived macrophages to the Ly6Chi (Figure 2C) and Ly6Clo populations (Figure 2D), with an increase in the percentage of monocytes contributing to the Ly6Clo pool in the heart (Figure 2E) four days after MI in the cardiomyocyte treated group compared to the MI control

Summary

Introduction

Cardiovascular diseases are a major cause of morbidity and mortality in the world [1]. There is a variety of treatment options available ranging from pharmacological treatments, small molecules that stimulate endogenous regeneration, cell transplantation and immune modulation to heart transplantation Their potential to regenerate the ailing myocardium and vast troves of previously published literature has made stem cell transplantation a dominant candidate as a preclinical and clinical treatment strategy for MI [2]. The marginal benefit of these cell transplantation studies has been attributed to diverse reasons with no clear scope of improvement owing mainly to the lack of clarity on their mechanism of action. This roadblock has led to people questioning the future of stem cell therapy as a viable treatment option [3]

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