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• W3048641110 abstract "There are 26 million patients living with heart failure (HF), which is one of the primary causes of death worldwide. HF is a pathological process characterised by heart muscle damage leading to progressive deterioration of the heart’s pumping and/or filling capabilities. This process decreases cardiac output and results in an inability to meet metabolic demand and ultimately sudden cardiac death. The most common cause of HF is coronary artery disease like myocardial infarction (MI). The adult heart is the least regenerative organ in the body, hence heart muscle is never replaced after injury, making HF a chronic and incurable disease. The inability of the adult mammalian heart to regenerate represents a major limitation in cardiovascular medicine and HF management. Currently all medical therapies for HF seek to salvage viable cardiac tissue, prevent maladaptive remodelling or improve the contractility of the failing heart but crucially, no cardioregenerative therapies exist. As such, a new class of regenerative therapeutics would revolutionise the treatment of HF patients, for which there have not been any approvals for new drug classes for 20 years.In comparison to the adult heart, recent studies indicate that neonatal mice retain a remarkable capacity for cardiac regeneration after catastrophic heart injury. This regenerative capability is rapidly lost in postnatal life, which reflects a developmentally regulated transition of cardiomyocytes (the contractile cells of the heart) from hyperplasic to hypertrophic growth during cardiac maturation. It is hypothesised that factors which potentiate neonatal cardiac regeneration could be used to transform the post-mitotic adult heart into a neonatal-like pro-proliferative state and facilitate adult cardiomyocyte proliferation and, thereby, cardiac regeneration. However, the mechanisms that mediate cardiac regeneration in the neonatal period and that govern loss of regenerative capacity during postnatal development are poorly characterised and, even with the most potent mitogens, complete regeneration of the adult heart remains elusive.To solve these problems, there was need for a comprehensive identification and comparative analysis of neonatal regenerative and adult non-regenerative gene programs. It is recognised that the neonatal cardioregenerative process not only requires the proliferation of the heart parenchyma, the cardiomyocyte, but non-cardiomyocyte cell types also participate in the regenerative processes during post-injury angiogenesis, extracellular matrix remodelling, and injury site debridement. Therefore, the four predominant cardiac cell populations (cardiomyocytes, fibroblasts, endothelial cells, and leukocytes) were isolated from regenerative neonatal (postnatal day 1) and non-regenerative adult hearts (postnatal day 56) with and without MI, generating 64 RNA-sequencing (RNA-seq) samples for transcriptional analyses. This cardiac regeneration, postnatal development and post-injury transcriptional dataset represents a unique resource for the cardiovascular field that may enable identification of therapeutic avenues for heart regeneration.Chapter 3 of this Thesis delineates the transcriptional networks associated with neonatal regenerative and adult fibrotic responses to injury. Adult cardiomyocytes were the most transcriptionally distinct cell type and, surprisingly, neonatal myocytes were found to be more transcriptionally similar to other non-myocyte cell types than adult cardiomyocytes. Neonatal cardiomyocytes did not deploy a regenerative gene program following injury, rather both infarcted and sham operated neonatal myocytes expressed cell-cycle machinery and appeared to be in a transcriptionally permissive state for cardiac proliferation and regeneration. Unlike adult fibroblasts and leukocytes, adult cardiomyocytes and endothelial cells were incapable of acquiring a neonatal-like transcriptional signature following injury. This observation challenged the long-held dogma that adult myocytes revert to a foetal/neonatal-like transcriptional state during the pathogenesis of cardiac hypertrophy and HF. The regenerative gene network contained a suite of cell-cycle associated genes, which were predicted to be controlled by a host of transcription factors (including Myc, E2f class of transcriptional factors, Foxm1 and Mybl2). Assessment of the cardiomyocyte chromatin landscape identified the targets of these transcription factors became epigenetically condensed during postnatal cardiomyocyte development, intimating that perhaps cardiomyocytes are epigenetically constrained to prevent proliferation and thereby cardiac regeneration in adulthood.Chapter 4 focused on identifying molecular drivers of cardiomyocyte proliferation using transcriptomics. One of the most consistently associated signalling networks active in neonatal cells during development was Wnt/beta-catenin. Transcriptional analysis and immunostaining confirmed that canonical Wnt/beta-catenin signalling was rapidly shutdown during postnatal cardiomyocyte development in vivo. Moreover, stimulation of canonical Wnt/beta-catenin signalling by glycogen synthase kinase 3 (GSK3) inhibition profoundly augmented human embryonic stem cell-derived cardiomyocyte proliferation in vitro. Similarly, delivery of constitutively active beta-catenin (caBCAT) potentiated neonatal mouse cardiomyocyte proliferation in-vivo. Conversely, pharmacological inhibition of beta-catenin abrogated neonatal cardiomyocyte proliferation in vivo. Through RNA-seq and chromatin immunoprecipitation-sequencing (ChIP-Seq) of beta-catenin’s transcriptional mediator, Tcf7l2, 20 beta-catenin target genes common to both human and mouse myocytes were identified. In contrast with these effects in immature proliferative cardiomyocytes, caBCAT delivery following adult MI did not induce cardiomyocyte proliferation, although cardiac function was markedly improved.Therefore, beta-catenin has divergent roles in the immature cardiac tissues (like human embryonic stem cell (ESC)-derived cardiac organoids and neonatal mouse hearts) and the mature adult heart, but it was unclear how beta-catenin signalling was repurposed during postnatal maturation from being a cardioregenerative to cardioprotective stimulus. This thesis also sought to identify a molecular mechanism underlying the suppression of beta-catenin-stimulated adult cardiomyocyte proliferation. RNA-seq of caBCAT-treated adult cardiomyocytes uncovered a distinct cardioprotective response associated with modulation of metabolic and immune-responsive transcriptional networks. Therefore, beta-catenin drives distinct transcriptional programs in regenerative and non-regenerative cardiomyocytes. Bioinformatic interrogation of transcriptional and epigenetic datasets from human ESC-derived cardiomyocytes, neonatal and adult murine cardiomyocytes indicated that beta-catenin may be redirected from cell-cycle targets to cardioprotective and metabolic gene targets during adult cardiomyocyte maturation, preventing the beta-catenin-induced regenerative response in adult myocytes. It is postulated that co-option of cardiomyocyte mitogenic transcription factors to cardioprotective/metabolic target genes could be a universal mechanism underlying adult cardiomyocyte cell-cycle shutdown.In summary, this Thesis identifies the transcriptional mechanisms that mediate cardiac regeneration in the neonatal period and that govern loss of regenerative capacity during postnatal development. Moreover, this multicellular transcriptomic resource was used to identify potential mediators of heart regeneration by demonstrating that a regenerative candidate, beta-catenin, does indeed drive neonatal cardiomyocyte proliferation in vivo. In contrast, beta-catenin mobilises a cardioprotective transcriptional response in the mature adult heart. This thesis suggests that because neonatal and adult cardiomyocytes are so transcriptionally distinct, it is conceivable that for an adult myocyte to proliferate, these cells may be required to be reprogrammed into a more neonatal-like regenerative gene state to achieve bona fide regeneration." @default.
• W3048641110 created "2020-08-18" @default.
• W3048641110 creator A5061787466 @default.
• W3048641110 date "2020-07-24" @default.
• W3048641110 modified "2023-09-27" @default.
• W3048641110 title "Transcriptional regulation of mammalian heart regeneration" @default.
• W3048641110 doi "https://doi.org/10.14264/uql.2020.927" @default.
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