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Review
. 2024 Nov 1;25(21):11747.
doi: 10.3390/ijms252111747.

Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction

Erika Fiorino  1 , Daniela Rossin  1 , Roberto Vanni  1 , Matteo Aubry  1 , Claudia Giachino  1 , Raffaella Rastaldo  1
Affiliations
Review

Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction

Erika Fiorino et al. Int J Mol Sci. .

Abstract

Myocardial infarction (MI) is a critical global health issue and a leading cause of heart failure. Indeed, while neonatal mammals can regenerate cardiac tissue mainly through cardiomyocyte proliferation, this ability is lost shortly after birth, resulting in the adult heart's inability to regenerate after injury effectively. In adult mammals, the adverse cardiac remodelling, which compensates for the loss of cardiac cells, impairs cardiac function due to the non-contractile nature of fibrotic tissue. Moreover, the neovascularisation after MI is inadequate to restore blood flow to the infarcted myocardium. This review aims to synthesise the most recent insights into the molecular and cellular players involved in endogenous myocardial and vascular regeneration, facilitating the identification of mechanisms that could be targeted to trigger cardiac regeneration, reduce fibrosis, and improve functional recovery post-MI. Reprogramming adult cardiomyocytes to regain their proliferative potential, along with the modulation of target cells responsible for neovascularisation, represents promising therapeutic strategies. An updated overview of endogenous mechanisms that regulate both myocardial and coronary vasculature regeneration-including stem and progenitor cells, growth factors, cell cycle regulators, and key signalling pathways-could help identify new critical intervention points for therapeutic applications.

Keywords: Myocardial infarction; angiogenesis; cardiac regeneration; cardiomyocytes; endothelial cells; regenerative capacity; stem/progenitor cells; tissue repair.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of the response to myocardial injury in neonatal and adult mammalian models. After myocardial injury, different events can occur to regenerate the damaged heart. Neonatal mice (aged < 1 week) are capable of full regeneration and functional recovery after injury. In adult mice and humans, this regenerative capacity is lost, and the necrotic tissue after injury is replaced with a fibrotic scar.
Figure 2
Figure 2
Regulatory mechanisms involved in myocardial regeneration. It is widely debated whether cardiac progenitor cells (CPCs) possess the potential to differentiate into cardiomyocytes (CMs) in the adult heart. Mesenchymal stem cells (MSCs), through the paracrine release of exosomes, modulate the microenvironment, thereby promoting tissue regeneration. Growth factors, such as Fibroblast growth factors (FGFs), Neuregulin-1 (NRG-1), and Insulin-like growth factor (IGF), regulate CM proliferation by activating key molecular pathways, including WNT/β-catenin, PI3K/AKT, and JAK/STAT, which contribute to myocardial regeneration. Additionally, cell cycle regulators, such as cyclins, p53, and transcription factor T-box 20 (TBX20), govern CM cell cycle re-entry, supporting cardiac repair and regeneration.
Figure 3
Figure 3
Vascular regeneration after MI. Hypoxia triggers vascular regeneration in the damaged heart tissue. Hypoxia Inducible factor (HIFs) stimulate the production of vascular endothelial growth factor (VEGF), which promotes the degradation of the basement membrane, allowing the migration of ECs and the recruitment of stem/precursor cells. In particular, endothelial progenitor cells (EPCs), cardiac progenitor cells (CPCs), and mesenchymal stem cells (MSCs) are recruited to the site of injury, where they release a variety of pro-angiogenic factors and miRNAs. These signals stimulate pre-existing endothelial cells (ECs) to differentiate into tip and stalk cells, which drive the sprouting of new blood vessels. Additionally, the EPCs themselves are stimulated to differentiate into mature ECs, contributing directly to the formation of new vasculature. These mechanisms are mainly regulated by the DLL4/Notch signalling pathway driven by cytokines such as interleukins (IL-6 and IL-10) (as described in Section 4.2. paragraph). In the final stages, pericytes are recruited to stabilise and mature the newly formed vessels, ensuring proper vascular function in the healing heart.
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