GDF10 promotes rodent cardiomyocyte maturation during the postnatal period
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ABSTRACT:
PROVIDER: PRJNA1197527 | ENA |
REPOSITORIES: ENA
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Project description:Cardiomyocytes and cardiac fibroblasts undergo coordinated maturation after birth, and cardiac fibroblasts are required for postnatal cardiomyocyte maturation in mice. Here, we investigate the role of cardiac fibroblast-expressed Growth Differentiating Factor 10 (GDF10) in postnatal heart development. In neonatal mice, Gdf10 is expressed specifically in cardiac fibroblasts, with its highest expression coincident with onset of cardiomyocytes cell cycle arrest and transition to hypertrophic growth. In neonatal rat ventricular myocyte cultures, GDF10 treatment promotes cardiomyocyte maturation indicated by increased binucleation, downregulation of cell cycle progression genes and upregulation of cell cycle inhibitor genes. GDF10 treatment leads to an increase in cardiomyocyte cell size together with increased expression of mature sarcomeric protein isoforms and decreased expression of fetal cardiac genes. RNAsequencing of GDF10-treated NRVM shows an increase in gene expression related to myocardial maturation, including upregulation of sodium and potassium channel genes. In vivo, loss of Gdf10 leads to a delay in myocardial maturation indicated by a decrease in cardiomyocyte cell size and binucleation as well as increased mitotic activity at postnatal (P) day 7. Further, induction of mature sarcomeric protein isoform gene expression is delayed, and expression of cell cycle progression genes is prolonged. However, by P10 indicators of cardiomyocyte maturation and mitotic activity are normalized in Gdf10-null hearts relative to controls. Together, these results implicate Gdf10 as a novel crosstalk mediator between cardiomyocytes and cardiac fibroblasts, required for appropriate timing of cardiomyocyte maturation steps including binucleation, hypertrophy, mature sarcomeric isoform switch and cell cycle arrest in the postnatal period.
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Project description:Mammalian cardiomyocytes rapidly mature after birth, with hallmarks such as cell-cycle exit, binucleation, and metabolic switch to oxidative phosphorylation of lipids. The causes and transcriptional programs regulating cardiomyocyte maturation are not fully understood yet. Thus, we performed single cell RNA-seq of neonatal and postnatal day 7 rat hearts to identify the key factors for this process and found AP-1 as a key factor to regulate cardiomyocyte maturation. To find the mechanism of AP-1 during cardiomyocyte maturation, we performed RNA-seq analysis of neonatal rat ventricular cardiomyocytes and found Ap-1 promote cardiomyocyte maturation by regulating cardiomyocyte metabolism.
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Project description:Postnatal heart maturation is the basis of normal cardiac function and provides critical insights into heart repair and regenerative medicine. While static snapshots of the maturing heart have provided much insight into its molecular signatures, few key events during postnatal cardiomyocyte maturation have been uncovered.Here we processed bulkRNASeq and ChIPSeq of Cardiomyocyte at different postnatal time points.
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Project description:Postnatal heart maturation is the basis of normal cardiac function and provides critical insights into heart repair and regenerative medicine. While static snapshots of the maturing heart have provided much insight into its molecular signatures, few key events during postnatal cardiomyocyte maturation have been uncovered.Here we processed single cell RNASeq of Cardiomyocyte at different postnatal time points.
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Project description:Following birth, the heart undergoes intricate transitions in response to the altered environment, including shifts in energy metabolism and cytoarchitecture, such as the switch from glucose to lipid utilization and the transformation of fetal-to-adult sarcomeric gene isoforms, all aimed at achieving functional maturation. These adaptations facilitate efficient energy production and cardiac contraction, enabling the heart to effectively pump blood throughout the body. Although the early postnatal period is widely recognized as a critical phase for cardiomyocyte maturation, the precise mechanisms initiating and orchestrating this process remain elusive. Using in vivo and in vitro models incorporated with multi-omic analyses, we here show that Mettl1 is a critical regulator in postnatal cardiomyocyte maturation. We demonstrate that Mettl1 is required for the proper ketogenesis in cardiomyocyte maturation via regulating Hmgcs2 translation. Loss of Mettl1 leads to aberrant metabolic reprogramming and subsequent cardiomyocyte immaturation through the deficiency in lysine β-hydroxybutyrylation of TCA cycle-related proteins.
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Project description:To date, there have been limited high quality libraries of cardiomyocyte maturation during the perinatal period, in part owing to the difficulty of isolating large perinatal cardiomyocytes. We previously developed a method utilizing large-particle fluorescent activated cell sorting (LP-FACS) to isolate adult cardiomyocytes for single cell RNA-seq (Kannan et al., Circ Res, 2019). We utilize this method to generate a reference of perinatal cardiomyocyte maturation.
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