Myocardial infarction (MI) represents the most prevalent cardiovascular disease worldwide [1]. From a pathological perspective, MI is defined as cardiomyocyte (CM) cell death due to lack of oxygen supply, i.e., an ischemic event [2]. Ischemia leads to the necrosis and cell death of the affected myocardium. Moreover, during the reperfusion process, the sudden influx of oxygenated blood drives the generation of reactive oxygen species (ROS), promoting oxidative stress and an extra wave of cell death [3]. As it is well known, the adult human heart has low levels of cardiomyocyte proliferation, thereby limiting its healing capacity. However, it must be considered that if the ischemic process is shorter than 20 min, CMs can survive after the restoration of coronary flow, while longer ischemic periods facilitate a process wherein millions of CMs lose their contraction potential and die. These events promote pro-inflammatory scenarios within the infarcted area and cardiac fibroblasts (CFs) become activated, generating a fibrotic scar. More concretely, when MI occurs and the necrosis process has started, an inflammatory response is prompted by the CMs death. Pointedly, in the first wave of heart healing, necrotic cells must be cleared away by the proinflammatory extracellular-matrix (ECM)-degrading component; this process is known as efferocytosis [4]. Afterwards, inflammation is deactivated, and ECM deposition is activated to form the new scar [4]. These two processes are well coordinated and involve fine-tuned cross-talk among different cell types, such as cardiac myocytes, neutrophils, macrophages, fibroblasts, endothelial cells, and nerve cells, among which macrophages and fibroblasts are the two cell populations with the most important roles during the post-MI response. Finally, inflammation and scar formation lead to a loss of contractile function, which eventually induces heart failure (HF) ^[3][5][3,5].

In injured cardiac cells, an inflammatory process is triggered as a consequence of the activation of the Toll receptor (TLR) and/or nuclear factor-κB (NF-κB signaling pathways through the modulation of SOCS3 (suppressor of cytokine signaling 3) ^[6][7][8][6,7,8]. In the inflammatory phase, necrotic CMs release danger-associated molecular patterns (DAMPs). These molecules bind to their receptors in the surviving parenchymal cells and infiltrating leukocytes, thereby triggering the delivery of inflammatory actors, i.e., inflammatory cytokines such as CXC chemokines for neutrophil chemoattraction, CC chemokines that attract monocytes and T-lymphocytes, cell adhesion molecules, and complement factor B [4]. The expression of the pro-inflammatory genes is driven by DAMP–receptor binding, which induces an intracellular signaling pathway that leads to the activation of mitogen-activated protein kinases (MAPKs) and NF-κB [4].

At the cellular level, CMs, immune cells, vascular cells, and fibroblasts are key actors in the inflammatory response, although their precise roles remain largely unknown. Necrotic CMs are responsible for DAMPs’ release in the infarcted area, while the activation of endothelial cells is needed for the extravasation of leukocytes as neutrophils [9]. Emigrated neutrophils become the predominant cell type in the infarct zone within the first 24 h after MI and aid in the clearance of dead cells and matrix debris from the infarct zone. After 7 days post-MI, neutrophil levels decline due to the reduction in neutrophil extravasation by an anti-inflammatory process; however, the fibrotic response is enhanced, promoting HF ^[4][10][4,10]. Monocytes are immune cells that can differentiate into macrophages [11], and phagocytosis is one of their principal functions [12]. Resident macrophages are a heterogeneous population within the adult heart [13]. Like neutrophils, macrophages have a polarized status depending on their function. M1 macrophages play a pro-inflammatory role on day 1 post-MI, with phagocytic and proteolytic functions. Later, M1 macrophages change into M2 macrophages, which perform an anti-inflammatory and reparative role around day 7 post-MI due to the release of cytokines ^{[10][14][15][16][17]}[10,14,15,16,17]. It is essential to highlight that M1 macrophages induce a positive effect by producing pro-inflammatory exosomes (M1-exos) that accelerate injury repair after MI and promote angiogenesis [18]. However, if such M1 macrophages’ effect is maintained over time, it can trigger ECM degradation [19], thus decreasing the capacity for regeneration ^[20][21][20,21].

Concerning CFs, it is important to highlight that they represent an abundant population of cells in the adult mammalian myocardium that maintain homeostatic ECM conditions. However, after the release of DAMPs, CFs become activated, secreting cytokines and chemokines that may prevent fibrotic scar formation before cell death, and matrix debris are eliminated from the infarct zone [4]. Furthermore, several studies have demonstrated tight cross-talk among macrophages, neutrophils, fibroblasts, and endothelial cells [10]. Finally, during the inflammation process, the ECM plays an essential role as a structural scaffold and in the transduction of molecular signals, wherein it induces cytokine and chemokine segregation by endothelial and immune cells [4].

As mentioned before, the infarct zone is cleared of dead cells and matrix debris during the inflammation process. This step is followed by a proliferative phase that leads to cardiac repair, in which anti-inflammatory pathways are activated and myofibroblasts and vascular cells infiltrate the wounded area. It is necessary to suppress the inflammatory process for cardiac repair because a lack of optimal preservation of the cardiac structure could entail worse effects at the functional level [5]. During the clearance of dead cells, anti-inflammatory cytokines are released; concomitantly, infiltrated neutrophils undergo apoptosis [5]. After the inflammatory response, CFs are the main cell type within the infarcted area, and a phenotypic change occurs, where CFs transdifferentiate into myofibroblasts. These cells, which undergo increased synthesis of both structural and matricellular ECM proteins, present a proliferative phenotype and high expression of contractile proteins, such as α-smooth muscle actin (SMA) [22]. This transdifferentiation process is mediated by the activation of the transforming growth factor β (TGF-β), the deposition of fibronectin and other matrix proteins, and the removal of the pro-inflammatory inductor IL-1β [22].

Transcriptional regulation and its associated regulatory mechanisms are key components of cardiac regeneration. Several laboratories have deciphered the role of different transcription and growth factors that have the ability to maintain, in neonatal mice, or diminish, in adult mice, cardiac regenerative capacity [23]. A few years ago, Porrello’s lab analyzed the different transcriptional networks as well as signaling pathways and cellular processes in adult and neonatal injured hearts [24]. They found that neonatal CMs were enriched in transcription factors related to the cell cycle, such as E2f1 and Foxm1. In contrast, adult CMs were enriched in transcription factors related to autophagy, such as Tfeb (transcription factor EB), Amfr (autocrine motility factor receptor), Gabarap (GABA-type-A-receptor-associated protein), and oxidative stress-related genes such as Sod1 (superoxide dismutase 1) [24].

Interestingly, follistatin-like 1 (Fstl1) is expressed in the normal epicardium in mice, although its expression is reduced after cardiac injury is triggered in the myocardium. It has been evidenced that Fstl1 derived from epicardial cells promotes the proliferation of CMs. However, Fslt1 from the myocardium have lost this ability, probably due to post-translational modifications [25]. In the same line, Neuregulin1 (Nrg1) modulates CM proliferation in mammals, and its administration improves cardiac regeneration. This process seems to be mediated by an NRG1 receptor, namely, Erbb2 (erb-b2 receptor tyrosine kinase 2), whose expression dramatically diminishes in neonatal mice one week after birth [26]. In contrast, Erbb2 levels in adult zebrafish are maintained, thereby contributing to the preservation of cardiac regeneration via the modulation of Nrg1 levels [26]. Moreover, it must be considered that chromatin remodeling is associated with the inability of adult CMs to recapitulate neonatal proliferative programs. In neonatal injured CMs, a euchromatic state was found within genomic regions related to the cell cycle and inflammation genes; however, these euchromatic regions become more condensed in postnatal and adult injured CMs [24]. Overall, these studies provide an initial demonstration of the important contributions of inductive and transcriptional regulatory mechanisms during cardiac regeneration.

The molecular bases that govern cardiac regeneration are very complex, including both coding RNAs and non-coding RNAs (ncRNAs) as pivotal modulators. Researchers began addressing the impacts of non-coding RNAs some years ago, and it was through such research that it was discovered that they are powerful regulators of a multitude of cellular and pathological processes such as MI, hypertrophy, HF, and arrhythmias [27]. ncRNAs are functional RNA molecules (without protein-coding functions) that play an essential role in distinct biological and physiological processes as well as pathological disorders [28]. According to the number of nucleotides contained and their characteristics [28], ncRNAs are classified into (i) small non-coding RNAs (≤200 nucleotides), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), piwi-interacting RNAs (piRNAs), and transfer RNA (tRNAs); (ii) long non-coding RNAs (>200 nucleotides), including intronic, enhancer, circular, and intergenic lncRNAs; and (iii) circular RNA (circRNA), which lacks free ends and comprises a wide range of ncRNAs. This third emerging class is produced by a non-canonical splicing event (back-splicing), a process in which a downstream splice-donor site is covalently linked to an upstream splice-acceptor site. The canonical function of miRNAs is to modulate gene expression at the post-transcriptional level by recognizing and binding to target mRNAs and triggering their degradation ^[29][30][29,30]. Several studies have demonstrated that miRNAs are closely related to inflammation, fibrosis, and angiogenesis after MI ^[31][32][31,32]. The molecular mechanisms of long non-coding RNAs (lncRNA) are more complex than those of miRNAs because lncRNAs can exert their functions both at the transcriptional and post-transcriptional levels, interacting with all types of RNA molecules, proteins, and different chromatic modulators [33]. The participation of lncRNAs in MI has been recently evidenced. The genome-wide profiling of the cardiac transcriptome after MI has evidenced deregulated heart-specific lncRNAs [34]. Finally, circRNAs act by binding to proteins or miRNAs, interfering with them and blocking their function [35]. Evidence has demonstrated that circRNAs’ expression is impaired after MI [36]. Scientists from different countries found that circulating ncRNAs are sensitive biomarkers for cancer and other kinds of disease, including MI. These findings indicate that the identified biomarkers for MI offer great potential for clinical applications [37].

Within the MI context, the ability to link ncRNAs with the main cardiac gene-regulatory networks that drive the main biological processes activated after injury, such as inflammation and fibrosis, may provide a new opportunity for therapeutic intervention via regenerative medicine applied to the heart. The generation of new knowledge about this pathological process has become the primary concern within the field of cardiovascular research due to the high socioeconomic burden of acute MI and its chronic consequences in surviving patients.