GDF10 promotes rodent cardiomyocyte maturation during the postnatal period
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE284190 | GEO | 2025/02/11
REPOSITORIES: GEO
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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.
2021-12-01 | GSE182422 | GEO
Project description:Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon coculture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration.
2020-04-20 | GSE122706 | GEO
Project description:During the postnatal period in mammals, the cardiac muscle transitions from hyperplasic to hypertrophic growth, the extracellular matrix (ECM) undergoes remodeling, and the heart loses regenerative capacity. While ECM maturation and crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes (CM) have been implicated in neonatal heart development, not much is known about specialized fibroblast heterogeneity and functions in the early postnatal period. In order to better understand CF functions in heart maturation and postnatal cardiomyocyte cell cycle arrest, we have performed gene expression profiling and ablation of postnatal CF subpopulations. Fibroblast lineages expressing Tcf21 or Periostin were traced in transgenic GFP reporter mice and their biological functions and transitions during the postnatal period were examined in sorted cells using RNAseq. A subpopulation of highly proliferative Periostin (Postn)+ CFs was found from postnatal day (P)1 to P11 but was not detected at P30. This population was less abundant and transcriptionally different from Tcf21+ resident CFs, which persist in the mature heart. The Postn+ subpopulation preferentially expresses genes related to cell proliferation and neuronal development, while Tcf21+ CFs differentially express genes related to ECM maturation at P7 and immune crosstalk at P30. Ablation of the Postn+ CFs from P0 to P6 led to altered cardiac sympathetic nerve patterning and a reduction in CM binucleation, maturation, and hypertrophic growth. Thus, postnatal CFs are heterogeneous and include a transient proliferative Postn+ subpopulation required for cardiac nerve development and cardiomyocyte maturation soon after birth.
2020-08-05 | GSE144587 | GEO
Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
2024-04-03 | PXD050996 | Pride
Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
2024-04-03 | PXD050990 | Pride
Project description:The direct conversion, or trans-differentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provide promising ways of cardiac regeneration. However, genetic manipulations are still not desirable in real clinical applications. we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts with only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Microarray-bassed gene expression patterns of Mouse embryonic fibroblasts (MEFs), CiCMs, and cardiomyocytes(CMs) indicated a clear transition from dividing MEFs to differentiated cardiomyocyte-like state in CiCM samples.
2015-08-23 | GSE69924 | GEO
Project description:The direct conversion, or trans-differentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provide promising ways of cardiac regeneration. However, genetic manipulations are still not desirable in real clinical applications. we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts with only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Microarray-bassed gene expression patterns of Mouse embryonic fibroblasts (MEFs), CiCMs, and cardiomyocytes(CMs) indicated a clear transition from dividing MEFs to differentiated cardiomyocyte-like state in CiCM samples. Mouse embryonic fibroblasts were treated with a small-molecule combination CRFVPT (10 μM CHIR99021 (C); 10 μM RepSox (R); 50 μM Forskolin (F); 0.5 mM VPA (V); 5 μM Parnate, (P); 1 μM TTNPB (T)) to induce transdifferentiation to chemical-induced cardiomyocyte-like cells. CiCMs beating clusters were picked at day 24 for analysis. MEFs were isolated from mouse embryos, and CMs were isolated from mouse hearts. Total RNA of MEFs, CiCMs and CMs were extracted and hybridization on Affymetrix microarrays.
2015-08-23 | E-GEOD-69924 | biostudies-arrayexpress
Project description:The mammalian heart undergoes major transitions during postnatal life to acquire the physiological properties of an adult organ. Postnatal life imposes numerous adaptations including electrophysiological, structural and metabolic maturation of cardiomyocytes1, which occur coincident with loss of proliferative capacity and regenerative potential2,3. The discovery of key upstream drivers of cardiomyocyte maturation and cell cycle arrest remains one of the most important unanswered questions in cardiac biology. Discovery of these drivers would facilitate current attempts to promote cardiomyocyte maturation in vitro for drug discovery and to de-differentiate adult cardiomyocytes in vivo for regenerative medicine. A recent study has suggested that the shift from a low oxygen environment in utero towards a high oxygen environment after birth acts as a key trigger for cardiomyocyte cell cycle exit4. Moreover, it was recently demonstrated that proliferative adult cardiomyocytes reside in a hypoxic niche5 and that exposure of adult mice to gradual hypoxemia is sufficient to drive cell cycle re-entry and regeneration following infarction6. However, it is currently unclear whether postnatal changes in oxygen tension or the associated shifts in cardiomyocyte metabolism are sufficient to promote maturation and cell cycle arrest as human pluripotent stem cell (hPSC)-derived cardiomyocytes fail to mature when cultured at 21% oxygen7,8. There are considerable changes in metabolic substrate provision during early postnatal life. The mammalian heart relies on high concentrations of carbohydrates and the presence of insulin in utero but later switches to fatty acid dominated substrates present in milk and low insulin levels post-birth9. In order to adapt to these changes in substrates, cardiomyocytes upregulate the genes required for fatty acid oxidation after birth10. The importance of these metabolic adaptations for cardiomyocyte maturation has been difficult to study because genetic disruption of fatty acid oxidation components in vivo can have a broad range of negative health impacts11. Therefore, there is a need to develop alternative approaches for studying the impact of cardiomyocyte metabolism on the maturation process. hPSCs are now widely used for the generation of defined human somatic cell types, including cardiomyocytes. These cardiomyocytes have now been used extensively for developmental studies, drug screening, disease modeling, and heart repair. However, lack of maturity and inappropriate responses to pharmacological agents have been identified as limitations in 2D or embryoid body based differentiation strategies12. To improve maturity of hPSC-derived cardiomyocytes, long-term culture can be used13, although long-term cultures may not be amenable to high-throughput screening applications and adult-like maturity is still not achieved14. In an effort to better simulate heart muscle structure and function, cardiac tissue engineering to form 3D engineered heart tissue has been used15-19. However, despite these recent advances in human cardiac tissue engineering, cardiac tissues derived from hPSC still lack many features of fully mature adult heart tissue20. Moreover, engineered heart tissue fabrication, culture, mechanical loading and pacing protocols, and analysis methods using organ baths are costly, labor intensive, and the multiple handling steps induce variability. In order to facilitate higher-throughput experiments, platforms for engineered heart tissue production have been miniaturized, however, screening experiments using semi-automated force of contraction analyses have only been published in 24-well plate formats21. Therefore, we developed a novel 96-well device, the heart dynamometer (Heart-Dyno), for high-throughput functional screening of human cardiac organoids (hCOs) to facilitate screening on a larger scale. The Heart-Dyno is designed to facilitate automated formation of dense muscle bundles from minimal cells and reagents while also facilitating culture and automated force of contraction analysis without any tissue handling. Using the Heart-Dyno, we define serum-free 3D culture conditions that promote structural, electrophysiological, metabolic and proliferative maturation of hPSC-derived cardiac organoids. Furthermore, we uncover a metabolic mechanism governing cardiomyocyte cell cycle arrest through repression of a β-catenin and YAP1 dependent signalling.
2017-11-21 | PXD005736 | Pride
Project description:The acquisition of knowledge pertaining to the molecular mechanisms that govern cardiomyocyte (CM) proliferation would enable the creation of novel approaches to promote cardiac regeneration in adult individuals, a crucial therapeutic objective that has yet to be accomplished. The limited regenerative response observed in adult myocardium may be attributed, in part, to the relatively low proliferative capacity of cardiomyocytes. The comprehension of cardiomyocyte division is a complex undertaking, as cardiomyocytes are capable of entering the cell cycle but are unable to complete cell division. Our research revealed that the induction of cardiac cytoskeleton changes by Blebbistatin result in the entry of cardiomyocytes entry into the cell cycle but, followed by cell cycle arrest at the G2/M phase. Sirt1 is identified as a potential mediator of the binucleation process in neonatal rat cardiomyocytes, which is regulated by the cardiomyocyte cytoskeleton. Furthermore, the distribution of H3K9me3 in cardiomyocytes with varying nuclear numbers and treatments indicates a significant involvement in the formation of binucleated cardiomyocytes.
2024-06-30 | GSE262438 | GEO
Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
2024-04-02 | GSE261628 | GEO