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Review
. 2016 Oct 14:3:40.
doi: 10.3389/fcvm.2016.00040. eCollection 2016.

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts

Ivana Zlatanova  1 , Cristina Pinto  1 , Jean-Sébastien Silvestre  1
Affiliations
Review

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts

Ivana Zlatanova et al. Front Cardiovasc Med. .

Abstract

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases.

Keywords: cardiac; cardiovascular diseases; inflammation; myocardial infarction; myocytes; regeneration; remodeling pathways.

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Figures

Figure 1
Figure 1
Immune cell stimulation is among the earliest responses detectable in the injured cardiac tissue and plays an instrumental role in the coordination of multiple processes governing cardiac remodeling. In animal models, the number, type, and activation state of the different subclasses of inflammatory cells dictate their impact on cardiac repair leading to either positive or deleterious cardiac remodeling.
Figure 2
Figure 2
In experimental models of MI, monocytes/macrophages fine-tune the balance between proliferation and repair and have been shown to promote cardiomyocytes refreshment after cardiac injury. Cardiac regeneration can rely on the permissive environment for cellular proliferation induced by extracellular matrix deposition and activation of the vascular as well as the nervous compartment. One can also speculate that resident stem cells activation could also participate to cardiomyocytes refreshment in this setting. To add on complexity, resident macrophages of embryonic origin have drawn significant attention due to their counteracting roles on injury-induced inflammatory response and subsequent capacity for cardiac repair and regeneration.
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