Research Progress on Myocardial Regeneration: What is New?
Ischemic heart disease (IHD) remains a leading cause of morbidity and mortality worldwide, with myocardial infarction (MI) being its most severe manifestation. MI typically results in the loss of substantial cardiac tissue, which is subsequently replaced by fibrous scar tissue, leading to myocardial remodeling, cardiac dysfunction, and eventual heart failure. Therefore, reducing the fibrous scar area and promoting myocardial regeneration are crucial for reversing or delaying the disease course post-MI. This article reviews the latest research progress on myocardial regeneration, focusing on the mechanisms involved in neonatal cardiomyocyte (CM) regeneration and potential therapeutic strategies for promoting CM regeneration in adults.
The regeneration capacity of CMs is retained in neonatal mouse hearts but is limited in adult mouse hearts. Neonatal mice within seven days post-birth can fully regenerate their hearts after injury, including MI, leading to complete recovery of cardiac function and structure within a month. However, this regenerative ability is rapidly lost after the seventh day postpartum. Studies have shown that neonatal humans may also possess this intrinsic ability to replenish damaged myocardium and fully recover cardiac function after myocardial injury. Understanding the mechanisms of regeneration in neonatal CMs after MI provides theoretical support for promoting heart repair in adult mammals.
Cell cycle regulators play a significant role in CM proliferation. The cell cycle in mammals is regulated by a complex set of proteins, including cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors (CDKIs), CDK-activated kinases (CAK), and retinoblastoma (Rb). Overexpression of cyclin A2, cyclin D2, and cyclin B can induce DNA synthesis and CM mitosis in adult mammals. Knockout of p21, p27, and p57 genes may induce active proliferation in resting adult CMs after MI. Recent studies have shown that overexpression of CDK1, CDK4, cyclin B1, and cyclin D1 can effectively induce CM proliferation in adult mice, rats, and humans.
Transcription factors (TFs) also play crucial roles in CM proliferation after injury. Myeloid ecotropic viral integration site 1 (Meis1) is associated with hemopoiesis and cardiac development at the embryonic stage and plays a negative role in postpartum CM cell cycle arrest. Deletion of Meis1 in CMs of neonatal mice extends the CM proliferation window after heart injury, while overexpression of Meis1 inhibits CM proliferation. Other TFs, such as E2F2 and T-box 20 (Tbx20), may also promote CM proliferation after MI in adult mice.
Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are emerging as important regulators in CM proliferation and regeneration. Inhibition of miRNA-15 family, miRNA-34a, and miRNA-128 can promote CM proliferation and cardiac function recovery after MI. Conversely, miRNA-590, miRNA-199, miRNA-17–92 cluster, miRNA-204, and miRNA-302-367 can induce CM proliferation. lncRNAs such as ECRAR and CPR, and circRNAs like Nfix, also play significant roles in CM proliferation and cardiac repair.
The Hippo signaling pathway, an evolutionarily conserved pathway, is crucial for CM proliferation and regeneration. The terminal effectors of the Hippo pathway, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), promote cell proliferation, survival, and metabolic function. Activation of YAP or inhibition of the Hippo pathway can promote CM proliferation and cardiac repair after MI. Other signaling pathways, such as PI3K/AKT, JAK/STAT, Wnt/β-catenin, and p38 MAPK, also play potential roles in CM endogenous proliferation and regeneration.
Acute inflammation is closely related to CM proliferation in neonatal hearts. Induction of acute aseptic inflammation in neonatal mouse hearts can induce endogenous CM proliferation, which is suspended upon suppressing the immune response. The different outcomes of acute inflammation between neonatal and adult hearts might be due to the different sources of macrophages. Embryonic-derived cardiac resident macrophages are mobilized in neonatal mice after myocardial injury, while bone-marrow-derived macrophages are increased in adult mice.
Hypoxia and oxidative stress also influence CM proliferation. Mitochondrial reactive oxygen species (ROS) can induce CM cell cycle arrest, while cytoplasmic H2O2 induced by NADPH oxidase 4 (Nox4) can extend the time window for postpartum CM proliferation. Induction of systemic hypoxia can reduce mitochondrion-derived ROS, attenuate DNA damage, and activate CM mitosis. Hypoxia-inducible factors (HIFs) and HIF-regulating prolyl-hydroxylase domain enzymes (PHDs) may also play roles in CM proliferation induced by systemic hypoxia.
Protein kinases, such as glycogen synthase kinase 3-beta (GSK-3β) and erb-b2 receptor tyrosine kinase 2 (ERBB2), are involved in CM proliferation and cardiac regeneration. Inhibition of GSK-3β and induction of active ERBB2 can lead to CM proliferation and cardiac regeneration after MI. p38 mitogen-activated protein kinase (MAPK) plays a negative role in CM proliferation post-MI, and its inhibition can promote CM proliferation and regeneration.
Epigenetic regulation of CM proliferation is a new research direction. Post-translational modification of histones, such as DNA methylation, deacetylation, and phosphorylation, can affect the expression of adult cardiac cyclin. Recombinant growth factor neuregulin-1 (rNRG1) and the activation of complement receptor C5aR1 may also participate in CM regeneration in neonatal mice. Increased levels of circulating thyroxine can deprive the heart of the ability to regenerate in adult CMs.
In conclusion, endogenous proliferation of adult CMs may be a promising method to promote the recovery of cardiac function after MI. However, challenges such as understanding the interaction between reported mechanisms and overcoming methodological limitations must be addressed before clinical application. The multi-step preclinical and clinical trials can deal with these limitations and generate benefits for human beings.
doi.org/10.1097/CM9.0000000000000693
Was this helpful?
0 / 0