Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE64403 | GEO | 2014/12/20
SECONDARY ACCESSION(S): PRJNA270897
REPOSITORIES: GEO
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Project description:Rationale: Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective: The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results: We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions: Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. Comparison of transcriptional programs of primary myocardial tissues sampled from neonatal mice and murine hearts undergoing post-injury regeneration, along with in vitro ESC-differentiated cardiomyocytes
2014-12-20 | E-GEOD-64403 | biostudies-arrayexpress
Project description:Scar tissue that forms in the heart after cardiac injury, comprises an abundant number of non-excitable fibroblasts in close proximity to excitable myocytes, that are embedded within the matrix of the scar. Electrical coupling of fibroblasts and myocytes is known to occur and in vitro simulation studies have demonstrated that changes in fibroblast membrane potential can lead to myocyte excitability and susceptibility to arrhythmogenesis. However, the physiologic significance of electrical coupling between myocytes and fibroblasts in scar tissue, in the regulation of cardiac excitability and arrhythmogenesis in vivo is hotly debated and has never been demonstrated. Here, we genetically engineer a mouse that expresses the optogenetic cationic channel ChR2 exclusively in cardiac fibroblasts and not in cardiac myocytes. We subject the animal to cardiac injury and demonstrate that optical stimulation of scar tissue elicits cardiac excitability and induces arrhythmias. Connexin 43 (Cx43) is a gap junctional protein that is the most abundant connexin isoform in the heart and thought to mediate electrical coupling of fibroblasts and myocytes. Using genetic loss of function approaches, we show that Cx43 is not necessary for fibroblast-myocyte electrical coupling in vivo. CRISPR/Cas 9 mediated sequential deletion of the other highly expressed connexins also did not affect electrical coupling of fibroblasts and myocytes. Using computational modeling approaches, we show that gap junctional and non-gap junctional coupling mechanisms synergize in a functionally redundant manner to excite myocytes coupled to fibroblasts. These observations demonstrate that cardiac fibroblasts in scar tissue directly regulate cardiac excitability in vivo and can induce arrhythmogenesis. Our findings throw insight into the importance of electrical coupling of fibroblasts and myocytes in the genesis of scar associated cardiac arrhythmias.
2023-09-28 | GSE235434 | GEO
Project description:Inducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell-cell contact-dependent manner, however, it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used cultured human iPSC-derived cardiac myocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart development in vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.
2021-09-08 | GSE176142 | GEO
Project description:We used microarrays to detail genome-wide gene expression underlying cardiac myocyte pathologies and identified candidate genes and specific pathways affecting cardiac myopathies Keywords: transgenics, cardiac disease analysis Mouse heart atria were dissected for RNA extraction and hybridisation on Affymetrix microarrays. We sought to profile gene expression from the transgenic mouse models for non-transgenics (Ntg), dnPI3K (dominant negative for phosphoinositide 3-kinase), Mst1 (mammalian sterile 20-like kinase 1) and dnPI3K-Mst1 (double mutant) mouse models with a combined background of C57BL/6/FVB/N inbred strains. Pathological insults on cardiac myocytes are investigated
2010-04-07 | E-GEOD-12420 | biostudies-arrayexpress
Project description:Since the proliferative capacity of cardiomyocytes is extremely limited in the adult mammalian hearts, the irreversible loss of cardiomyocytes following cardiac injury markedly reduces cardiac function, leading to cardiac remodeling and heart failure. However, the early neonatal mice have a strong ability in cardiomyocyte proliferation and cardiac regeneration after heart damage such as apical resection. Besides of cardiomyocytes, non-myocytes in heart tissue also play important roles in the regeneration process. Previous studies showed that cardiac macrophages, regulatory T cells and CD4+ T cells are all involved in regulating the myocardial regeneration process. However, the roles of other cardiac immune cells in cardiac regeneration remains to be elucidated. B cells is a prominent immune cell in injured heart; here we discovered the indispensable function of cardiac B cells in improving cardiomyocyte proliferation and heart regeneration in neonatal mice.
2023-06-02 | GSE205115 | GEO
Project description:Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.
| PRJNA270897 | ENA
Project description:The mammalian heart is composed of a variety types of cells that can be roughly categorized into cardiomyocytes and non-myocytes. Instead of being bystanders of cardiac function, cardiac non-myocytes provide critical structural, mechanical and electrophysiological support to the working myocardium. However, the precise cellular identity and molecular features of the non-myocytes at single cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single cell multi-omics has the potential to unravel the molecular programs of cardiac non-myocytes underlying their cellular diversity. To characterize the molecular and cellular features of cardiac non-myocytes populations in the adult murine heart at single cell level. We applied single cell Assay for Transposase Aaccessible Chromatin using sequencing (scATAC-seq) in combination with high-throughput single cell RNA-seq (scRNA-seq) to map the epigenetic landscape and gene expression program of cardiac non-myocytes from adult murine heart. Through integrated dual-omics data analysis, we categorize the cardiac non-myocytes into 4 defined populations including endothelial cells, fibroblast, pericytes and immune cells with distinct chromatin accessibility patterns. Cis- and trans-regulatory factors for each cell type were identified. In particular, unbiased sub-clustering and functional annotation of the cardiac fibroblast (FB), indicated the heterogeneity and functionality of FB subtypes associated with cellular response, cytoskeleton organization and immune regulation. We further validated the expression and function of novel markers in major FB sub-populations and experimentally determined the distribution of the FB sub-populations in healthy and injured murine heart. In summary, we comprehensively characterized the non-myocyte cellular identity at the single-cell level and defined FB subpopulations by their functional states.
2021-04-21 | GSE157445 | GEO
Project description:The mammalian heart is composed of a variety types of cells that can be roughly categorized into cardiomyocytes and non-myocytes. Instead of being bystanders of cardiac function, cardiac non-myocytes provide critical structural, mechanical and electrophysiological support to the working myocardium. However, the precise cellular identity and molecular features of the non-myocytes at single cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single cell multi-omics has the potential to unravel the molecular programs of cardiac non-myocytes underlying their cellular diversity. To characterize the molecular and cellular features of cardiac non-myocytes populations in the adult murine heart at single cell level. We applied single cell Assay for Transposase Aaccessible Chromatin using sequencing (scATAC-seq) in combination with high-throughput single cell RNA-seq (scRNA-seq) to map the epigenetic landscape and gene expression program of cardiac non-myocytes from adult murine heart. Through integrated dual-omics data analysis, we categorize the cardiac non-myocytes into 4 defined populations including endothelial cells, fibroblast, pericytes and immune cells with distinct chromatin accessibility patterns. Cis- and trans-regulatory factors for each cell type were identified. In particular, unbiased sub-clustering and functional annotation of the cardiac fibroblast (FB), indicated the heterogeneity and functionality of FB subtypes associated with cellular response, cytoskeleton organization and immune regulation. We further validated the expression and function of novel markers in major FB sub-populations and experimentally determined the distribution of the FB sub-populations in healthy and injured murine heart. In summary, we comprehensively characterized the non-myocyte cellular identity at the single-cell level and defined FB subpopulations by their functional states.
2021-04-21 | GSE157444 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246741 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246740 | GEO