Non-coding RNAs in Cardiac Regeneration.
Ontology highlight
ABSTRACT:
SUBMITTER: Yuan T
PROVIDER: S-EPMC8024481 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Soon after birth, the regenerative capacity of the mammalian heart is lost, cardiomyocytes withdraw from the cell cycle and demonstrate a minimal proliferation rate. Despite improved treatment and reperfusion strategies, the uncompensated cardiomyocyte loss during injury and disease results in cardiac remodeling and subsequent heart failure. The promising field of regenerative medicine aims to restore both the structure and function of damaged tissue through modulation of cellular processes and regulatory mechanisms involved in cardiac cell cycle arrest to boost cardiomyocyte proliferation. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are functional RNA molecules with no protein-coding function that have been reported to engage in cardiac regeneration and repair. In this review, we summarize the current understanding of both the biological functions and molecular mechanisms of ncRNAs involved in cardiomyocyte proliferation. Furthermore, we discuss their impact on the structure and contractile function of the heart in health and disease and their application for therapeutic interventions.
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Project description:In the past two decades, thousands of non-coding RNAs (ncRNAs) have been discovered, annotated, and characterized in nearly every tissue under both physiological and pathological conditions. Here, we will focus on the role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ischemic heart disease (IHD), which remains the leading cause of morbidity and mortality in humans-resulting in 8.9 million deaths annually. Cardiomyocyte (CM) proliferation, differentiation, and survival in addition to neovascularization of injured tissues and the prevention of fibrosis are commonly regarded as critically important for the recovery of the heart following myocardial infarction (MI). An abundance of evidence has been accumulated to show ncRNAs participate in cardiac recovery after MI. Because miRNAs are important regulators of cardiac regeneration, the therapeutic potential of at least five of these molecules has been assessed in large animal models of human IHD. In particular, miRNA-based interventions based on miR-132 and miR-92a inhibition in related diseases have displayed favorable outcomes that have provided the impetus for miRNA-based clinical trials for IHD. At the same time, the functional roles of lncRNAs and circRNAs in cardiac regeneration are also being explored. In the present review, we will summarize the latest ncRNA studies aimed at reversing damage to the ischemic heart and discuss the therapeutic potential of targeting miRNAs, lncRNAs, and circRNAs to stimulate cardiac regeneration.
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Project description:A growing body of evidence indicates that cardiac regeneration after myocardial infarction can be achieved by stimulating the endogenous capacity of cardiomyocytes (CMs) to replicate. This process is controlled, both positively and negatively, by a large set of non-coding RNAs (ncRNAs). Some of the microRNAs (miRNAs) that can stimulate CM proliferation is expressed in embryonic stem cells and is required to maintain pluripotency (e.g. the miR-302∼367 cluster). Others also govern the proliferation of different cell types, including cancer cells (e.g. the miR-17∼92 cluster). Additional miRNAs were discovered through systematic screenings (e.g. miR-199a-3p and miR-590-3p). Several miRNAs instead suppress CM proliferation and are involved in the withdrawal of CMs from the cell cycle after birth (e.g. the let-7 and miR-15 families). Similar regulatory roles on CM proliferation are also exerted by a few long ncRNAs. This body of information has obvious therapeutic implications, as miRNAs with activator function or short antisense oligonucleotides against inhibitory miRNAs or lncRNAs can be administered to stimulate cardiac regeneration. Expression of miRNAs can be achieved by gene therapy using adeno-associated vectors, which transduce CMs with high efficiency. More effective and safer for therapeutic purposes, small nucleic acid therapeutics can be obtained as chemically modified, synthetic molecules, which can be administered through lipofection or inclusion in lipid or polymer nanoparticles for efficient cardiac delivery. The notion that it is possible to reprogramme CMs into a regenerative state and that this property can be enhanced by ncRNA therapeutics remains exciting, however extensive experimentation in large mammals and rigorous assessment of safety are required to advance towards clinical application.
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Project description:Myocardial infarction causes a massive loss of cardiomyocytes (CMs), which can lead to heart failure accompanied by fibrosis, stiffening of the heart, and loss of function. Heart failure causes high mortality rates and is a huge socioeconomic burden, which, based on diets and lifestyle in the developed world, is expected to increase further in the next years. At present, the only curative treatment for heart failure is heart transplantation associated with a number of limitations such as donor organ availability and transplant rejection among others. Thus, the development of cellular reprogramming and defined differentiation protocols provide exciting new possibilities for cell therapy approaches and which opened up a new era in regenerative medicine. Consequently, tremendous research efforts were undertaken to gain a detailed molecular understanding of the reprogramming processes and the in vitro differentiation of pluripotent stem cells into functional CMs for transplantation into the patient's injured heart. In the last decade, non-coding RNAs, particularly microRNAs, long non-coding RNAs, and circular RNAs emerged as critical regulators of gene expression that were shown to fine-tune cellular processes both on the transcriptional and the post-transcriptional level. Unsurprisingly, also cellular reprogramming, pluripotency, and cardiac differentiation and maturation are regulated by non-coding RNAs. In here, we review the current knowledge on non-coding RNAs in these processes and highlight how their modulation may enhance the quality and quantity of stem cells and their derivatives for safe and efficient clinical application in patients with heart failure. In addition, we summarize the clinical cell therapy efforts undertaken thus far.
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Project description:Non-coding RNAs (ncRNAs) are a large cluster of RNAs that do not encode proteins, but have multiple functions in diverse cellular processes. Mounting evidence indicates the involvement of ncRNAs in the physiology and pathophysiology of the central and peripheral nervous systems. It has been shown that numerous ncRNAs, especially microRNAs and long non-coding RNAs, are differentially expressed after insults such as acquired brain injury, spinal cord injury, and peripheral nerve injury. These ncRNAs affect neuronal survival, neurite regrowth, and glial phenotype primarily by targeting specific mRNAs, resulting in translation repression or degradation of the mRNAs. An increasing number of studies have investigated the regulatory roles of microRNAs and long non-coding RNAs in neural injury and regeneration, and thus a new research field is emerging. In this review, we highlight current progress in the field in an attempt to provide further insight into post-transcriptional changes occurring after neural injury, and to facilitate the potential use of ncRNAs for improving neural regeneration. We also suggest potential directions for future studies.
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Project description:The discovery of functional long non-coding RNAs (lncRNAs) changed their initial concept as transcriptional noise. LncRNAs have been identified as regulators of multiple biological processes, including chromatin structure, gene expression, splicing, mRNA degradation, and translation. However, functional studies of lncRNAs are hindered by the usual lack of phenotypes upon deletion or inhibition. Here, we used Drosophila imaginal discs as a model system to identify lncRNAs involved in development and regeneration. We examined a subset of lncRNAs expressed in the wing, leg, and eye disc development. Additionally, we analyzed transcriptomic data from regenerating wing discs to profile the expression pattern of lncRNAs during tissue repair. We focused on the lncRNA CR40469, which is upregulated during regeneration. We generated CR40469 mutant flies that developed normally but showed impaired wing regeneration upon cell death induction. The ability of these mutants to regenerate was restored by the ectopic expression of CR40469. Furthermore, we found that the lncRNA CR34335 has a high degree of sequence similarity with CR40469 and can partially compensate for its function during regeneration in the absence of CR40469. Our findings point to a potential role of the lncRNA CR40469 in trans during the response to damage in the wing imaginal disc.
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Project description:Cardiovascular diseases are a major health problem, and long-term survival for people diagnosed with heart failure is, still, unrealistic. Pathological cardiac hypertrophy largely contributes to morbidity and mortality, as effective therapeutic approaches are lacking. Non-coding RNAs (ncRNAs) arise as active regulators of the signaling pathways and mechanisms that govern this pathology, and their therapeutic potential has received great attention in the last decades. Preclinical studies in large animal models have been successful in ameliorating cardiac hypertrophy, and an antisense drug for the treatment of heart failure has, already, entered clinical trials. In this review, we provide an overview of the molecular mechanisms underlying cardiac hypertrophy, the involvement of ncRNAs, and the current therapeutic landscape of oligonucleotides targeting these regulators. Strategies to improve the delivery of such therapeutics and overcome the actual challenges are, also, defined and discussed. With the fast advance in the improvement of oligonucleotide drug delivery, the inclusion of ncRNAs-targeting therapies for cardiac hypertrophy seems, increasingly, a closer reality.
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