Single-Cell Imaging and Transcriptomic Analyses of Endogenous Cardiomyocyte Dedifferentiation and Cycling
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ABSTRACT:
PROVIDER: PRJNA530385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8757984.fastq.gz | Fastqsanger.gz | |||
| SRR8757985.fastq.gz | Fastqsanger.gz | |||
| SRR8757986.fastq.gz | Fastqsanger.gz |
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Project description:We have demonstrated previously that adult cardiomyocytes can dedifferentiate and proliferate when cultured in vitro. To determine if cardiomyocyte dedifferentiation and cell cycling/proliferation happens in vivo, we applied here a novel multi-reporter transgenic mouse model (aMH-CMerCreMer;mT/MG;aMHC-H2BBFP) carrying reporter genes for permanent cardiomyocyte lineage mapping and maturity (dedifferentiation) reporting. With this new model, we deciphered the cellular sources and processes of cardiomyocyte dedifferentiation and proliferation in adult hearts. In this study, we used single-nucleus RNA-sequencing to tackle the challenges in analyzing the highly heterogeneous heart cell populations, and obtained datasets for a large number of cardiac single nuclei (both myocytes and non-myocytes) for control and post-infarct hearts. We identified specific cell populations in the heart using distinct transcriptomic clusters, transgenic reporters for ACM lineage and dedifferentiation, as well as cell cycle markers. The results demonstrated that the dedifferentiation and cell cycle progression of pre-existing CMs was augmented in post-infarct hearts, with a number of signaling pathways and gene sets affected. This is the first study dissecting the transcriptomic profiles and signaling pathways associated with cardiomyocyte dedifferentiation and cycling/proliferation in vivo using unbiased high-throughput single-nucleus RNA-Seq analysis, in junction with novel cell lineage (e.g. cardiomyocyte) and phenotyping (e.g. dedifferentiation) transgenic model systems.
2019-07-02 | GSE128628 | GEO
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-07-02 | GSE129175 | GEO
Project description:Rationale: In virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We’ve previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells. Objective: To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. Methods and Results: Brief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. Conclusions: These data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.
2019-07-07 | GSE133904 | GEO
Project description:The Right Ventricular Fibroblast Secretome Drives Cardiomyocyte Dedifferentiation
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Project description:Near-complete reversal of ERBB2-driven cardiomyocyte dedifferentiation is driven by the Hippo pathway, restoring contractility whilst long-lasting conferring cardioprotection.
2023-02-01 | PXD038450 | Pride
Project description:Background: Long noncoding RNAs (lncRNAs) have emerged as critical regulators in cardiovascular biology, influencing cardiac development, remodeling, and regeneration. Zeb2os, a natural antisense transcript (NATs) of the Zeb2 gene, has been linked to these processes in various organs. While ZEB2 promotes cardiac repair, the role of Zeb2os in these processes remains unclear. This study investigates the role of Zeb2os in modulating ZEB2 expression and cardiac remodelling after ischemic injury. Methods: We used adeno-associated virus (AAV9) vectors to overexpress Zeb2os in mouse models of cardiac IR injury. RNA sequencing, immunofluorescence, and high-resolution respirometry were employed to evaluate the effects of Zeb2os delivery on gene expression, ZEB2 reactivation, cardiomyocyte phenotype, scar composition and mitochondrial function. Experiments in cultured cardiomyocytes under hypoxia further explored the regulatory dynamics between Zeb2os and Zeb2. Results: We identified Zeb2os as a hypoxia-responsive lncRNA that displays an inverse and oscillatory expression pattern with Zeb2 in both in vitro and in vivo models of cardiac injury. Functional experiments revealed that Zeb2os negatively regulates ZEB2 expression, impairing the cardiomyocyte dedifferentiation and metabolic remodelling necessary for effective repair. AAV9-mediated delivery of Zeb2os resulted in preserved sarcomere structure, altered scar composition, reduced expression of regenerative genes, and diminished cardiac function following injury. In contrast, silencing of Zeb2os increased ZEB2 protein expression, suggesting a potential therapeutic strategy to enhance repair. Mechanistically, modulation of Zeb2os levels inversely regulated ZEB2 protein expression, whereas ZEB2 modulation had no effect on Zeb2os levels, indicating a unidirectional regulatory axis between the two transcripts. Conclusions: Our findings identify Zeb2os as a stress-responsive inhibitor of ZEB2 reactivation that limits cardiomyocyte plasticity and hinders repair following ischemic injury. Given its specific activity under ischemic conditions, targeting os may represent a novel therapeutic strategy to enhance endogenous cardiac regeneration
2026-02-05 | GSE311091 | GEO
Project description:Zeb2os Hinders Cardiac Healing by Suppressing ZEB2 Reactivation and Cardiomyocyte Dedifferentiation
| PRJNA1368652 | ENA
Project description:Background: Long noncoding RNAs (lncRNAs) have emerged as critical regulators in cardiovascular biology, influencing cardiac development, remodeling, and regeneration. Zeb2os, a natural antisense transcript (NATs) of the Zeb2 gene, has been linked to these processes in various organs. While ZEB2 promotes cardiac repair, the role of Zeb2os in these processes remains unclear. This study investigates the role of Zeb2os in modulating ZEB2 expression and cardiac remodelling after ischemic injury. Methods: We used adeno-associated virus (AAV9) vectors to overexpress Zeb2os in mouse models of cardiac IR injury. RNA sequencing, immunofluorescence, and high-resolution respirometry were employed to evaluate the effects of Zeb2os delivery on gene expression, ZEB2 reactivation, cardiomyocyte phenotype, scar composition and mitochondrial function. Experiments in cultured cardiomyocytes under hypoxia further explored the regulatory dynamics between Zeb2os and Zeb2. Results: We identified Zeb2os as a hypoxia-responsive lncRNA that displays an inverse and oscillatory expression pattern with Zeb2 in both in vitro and in vivo models of cardiac injury. Functional experiments revealed that Zeb2os negatively regulates ZEB2 expression, impairing the cardiomyocyte dedifferentiation and metabolic remodelling necessary for effective repair. AAV9-mediated delivery of Zeb2os resulted in preserved sarcomere structure, altered scar composition, reduced expression of regenerative genes, and diminished cardiac function following injury. In contrast, silencing of Zeb2os increased ZEB2 protein expression, suggesting a potential therapeutic strategy to enhance repair. Mechanistically, modulation of Zeb2os levels inversely regulated ZEB2 protein expression, whereas ZEB2 modulation had no effect on Zeb2os levels, indicating a unidirectional regulatory axis between the two transcripts. Conclusions: Our findings identify Zeb2os as a stress-responsive inhibitor of ZEB2 reactivation that limits cardiomyocyte plasticity and hinders repair following ischemic injury. Given its specific activity under ischemic conditions, targeting os may represent a novel therapeutic strategy to enhance endogenous cardiac regeneration
2026-02-05 | GSE311093 | GEO
Project description:Zeb2os Hinders Cardiac Healing by Suppressing ZEB2 Reactivation and Cardiomyocyte Dedifferentiation [2]
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