Effects of RRAGD p.(Ser76Leu) variant in human induced pluripotent stem cell-derived cardiomyocytes gene expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE323990 | GEO | 2026/03/13
REPOSITORIES: GEO
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Project description:Our research has demonstrated the following: (1) Confirmed that MYH7 mutations D239N, H251N, G256E lead to hypercontractility in hiPSC-derived cardiomyocytes (hiPSC-CMs); (2) Increase in YAP’s nuclear localization in both hiPSC-CMs and patient tissue with MYH7 HCM mutations; (3) A correlation between YAP's nuclear localization and enhanced force generation; (4) Nuclear deformation as a mechanism enabling YAP's nuclear entry and activation; (5) Transcriptomic changes resulting from positive and negative modifications in force generation; and (6) A distinctive paracrine hypertrophic signal reliant on cardiomyocyte-cardiac fibroblast crosstalk. Our unique insights to the intricacies of hypertrophic cardiomyopathy phenotypes hold the potential to provide mechanistic clarity, informing potential therapeutic strategies.
2025-01-01 | GSE261296 | GEO
Project description:Methods: RNA-seq libraries were prepared using the Illumina TruSeq technology. The libraries were quantified and samples were multiplexed in each lane of the flowcell. Cluster generation was performed and then sequenced on the Illumina HiSeq2500 system. Reads were mapped on the Human Genome Reference (GRCh38) and normalized expression table was generated. Results: Among differentially expressed genes, compared with DMSO-treated hiPSC-CMs, 505 genes were upregulated in FM+WY+TID-treated hiPSC-CMs, with 72 genes commonly upregulated in both FM+WY+TID-treated hiPSC-CMs and LV groups and 949 genes were downregulated in FM+WY+TID-treated hiPSC-CMs and 2137 genes were downregulated in LV, with 437 genes downregulated in both FM+WY+TID-treated hiPSC-CMs and LV compared with DMSO-treated hiPSC-CMs . Conclusions: Data demonstrate increased expression of genes associated with many metabolic processes which are also highly enriched in human pediatric heart samples including many interconnected metabolic processes that are upstream of lipid metabolism and FAO, agreeing with the shift to FAO for energy utilization in more mature CMs, and decreased expression of genes involved in developmental processes, adhesion and signaling in both FM+WY+TID-treated hiPSC-CMs and LV. The overlap in both upregulated and downregulated genes in both groups confirmed an advanced degree of cardiomyocyte maturation in response to FM+WY+TID.
2019-01-30 | GSE125862 | GEO
Project description:Loss of the PR domain 16 (PRDM16) genetic locus has been suggested as the needed trigger for the development of left ventricular non-compaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM) in patients with 1p36 deletion syndrome. Furthermore, lack of Prdm16 in the murine heart has recently been shown to cause a spectrum of cardiomyopathy phenotypes. In spite of these advances, our understanding of the downstream transcriptional pathways regulated by PRDM16 that lead to these cardiac phenotypes is limited. OBJECTIVE: to unveil the downstream transcriptional pathways involved in the development of cardiomyopathy phenotypes associated with PRDM16 mutations/deletion in human and mice. METHODS AND RESULTS: We hypothesized that PRDM16 acts as an upstream regulator of key transcriptional pathways involved in cardiac maturation. Induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with a PRDM16 variant, cardiac tissue from mice expressing the human variant, mice with cardiac-specific deletion of Prdm16 and in vitro gain and loss of Prdm16 function were employed. Here we show that de novo pathogenic variants in PRDM16 are sufficient to cause LVNC in humans. In contrast, haploinsufficiency or complete deletion of Prdm16 in cardiomyocytes in mice led to pathological hypertrophy and dilated cardiomyopathy respectively. We demonstrated that PRDM16 regulates cardiac maturation through the maintenance of estrogen-related receptors (ERRs) expression. By contrast, PRDM16 acts as a supressor of transforming growth factor beta (TGFB) signaling. CONCLUSIONS: PRDM16 is a novel regulator of cardiac maturation acting upstream of ERRs and their regulators, and a suppressor of fibrotic signaling including TGFB.
2023-12-01 | GSE193877 | GEO
Project description:Loss of the PR domain 16 (PRDM16) genetic locus has been suggested as the needed trigger for the development of left ventricular non-compaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM) in patients with 1p36 deletion syndrome. Furthermore, lack of Prdm16 in the murine heart has recently been shown to cause a spectrum of cardiomyopathy phenotypes. In spite of these advances, our understanding of the downstream transcriptional pathways regulated by PRDM16 that lead to these cardiac phenotypes is limited. OBJECTIVE: to unveil the downstream transcriptional pathways involved in the development of cardiomyopathy phenotypes associated with PRDM16 mutations/deletion in human and mice. METHODS AND RESULTS: We hypothesized that PRDM16 acts as an upstream regulator of key transcriptional pathways involved in cardiac maturation. Induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with a PRDM16 variant, cardiac tissue from mice expressing the human variant, mice with cardiac-specific deletion of Prdm16 and in vitro gain and loss of Prdm16 function were employed. Here we show that de novo pathogenic variants in PRDM16 are sufficient to cause LVNC in humans. In contrast, haploinsufficiency or complete deletion of Prdm16 in cardiomyocytes in mice led to pathological hypertrophy and dilated cardiomyopathy respectively. We demonstrated that PRDM16 regulates cardiac maturation through the maintenance of estrogen-related receptors (ERRs) expression. By contrast, PRDM16 acts as a supressor of transforming growth factor beta (TGFB) signaling. CONCLUSIONS: PRDM16 is a novel regulator of cardiac maturation acting upstream of ERRs and their regulators, and a suppressor of fibrotic signaling including TGFB.
2023-12-01 | GSE193873 | GEO
Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs, prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day-30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, t-tubule density, calcium handling, and electrophysiology, many equivalent to day-60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof-of-concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery.
2022-08-04 | GSE187308 | GEO
Project description:Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors capable of inducing matured hiPSC-CMs to proliferate. However, the mechanism by which L-type calcium channel blockers promote hiPSC-CM proliferation remains unclear. Here we provide evidence that matured hiPSC-CMs possess plasticity to undergo dematuration in response to certain pharmacological compounds. Consistent with primary cardiomyocyte maturation during perinatal development, we found that centrosome disassembly occurs in hiPSC-CMs during plate-based, temporal, maturation. A small molecule screen identified Nitrendipine, an L-type calcium channel blocker, and 1-NA-PP1, a Src kinase inhibitor, as factors capable of inducing centrosome reassembly in a subpopulation of hiPSC-CMs. Furthermore, centrosome-positive hiPSC-CMs were more likely to exhibit cell cycle activity than centrosome-negative hiPSC-CMs. In contrast, neither Nitrendipine or 1-NA-PP1 induced centrosome reassembly, or cell cycle activity, in neonatal rat ventricular myocytes (NRVMs). Differential bulk transcriptome analysis indicated that matured hiPSC-CMs, but not NRVMs, treated with Nitrendipine or 1-NA-PP1 undergo dematuration. ScRNA transcriptome analysis supported that matured hiPSC-CMs treated with either Nitrendipine or 1-NA-PP1 undergo dematuration. Collectively, our results indicate that matured hiPSC-CMs, but not primary NRVMs, possess plasticity to undergo dematuration in response to certain pharmacological compounds such as L-type calcium channel blockers and Src-kinase inhibitors. This study shows that once mature, hiPSC-CMs may not maintain their maturity under experimental conditions and thus may have implications for experimental systems where the state of hiPSC-CM maturation is relevant.
2025-04-23 | GSE263350 | GEO
Project description:Transcriptional regulatory circuits that drive cardiomyocyte maturation are poorly understood. Human iPS cell-derived cardiomyocytes (hiPSC-CMs) have been shown to have fetal cardiomyocyte features in terms of metabolic gene expression profiles. Here we found that in hiPSC-CMs, overexpression of estrogen-related receptor gamma (ERRg) is sufficient to drive cardiomyocyte metabolic maturation programs including the induction of a number of oxidative mitochondrial metabolic genes.
2022-02-16 | GSE165966 | GEO
Project description:Adult cardiomyocytes are embedded within a highly organized myocardial microenvironment that imposes critical geometric cues essential for the alignment and distribution of organelles and the shaping of their unique, rectangular cellular morphology. Despite the association of cardiomyocyte disarray with human heart disease, the functional consequences of this cellular disorganization remain poorly understood. Here, we leveraged micropatterned substrates to promote structural alignment in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), contrasting the effects of mechanical alignment on mitochondrial form and function with hiPSC-CMs cultured under standard unconstrained conditions. Cardiomyocytes cultured under unconstrained conditions exhibited misaligned sarcomeres and a perinuclear mitochondrial distribution while micropatterned hiPSC-CMs developed linear myofibrils and reconfigured sarcomere and mitochondrial organization, which increased mitochondrial respiration without augmenting mitochondrial mass. Notably, micropatterned hiPSC-CMs exhibited an increased number of mitochondria-associated membranes, as determined by proximity ligation assays and transmission electron microscopy, suggesting enhanced interactions between the sarcoplasmic reticulum and mitochondria. Together, these findings demonstrate that mitochondrial-sarcoplasmic architecture and geometry are critical spatial features that ensure bioenergetic efficiency of cardiomyocytes. This work underscores the importance of cellular organization in cardiomyocyte metabolism and function, providing insights into the pathophysiology of cardiac diseases marked by cellular disarray.
2025-09-01 | GSE303313 | GEO
Project description:During cardiomyocyte (CM) maturation, the centrosome undergoes a dramatic structural reorganization whereby certain components, previously localized at the centrioles, become localized to the nuclear envelope. Here, we generated a scRNA-seq data set of iPSC-CMs and identified impaired CM maturation as a key dysregulated process underlying a case of congenital dilated cardiomyopathy
2022-03-05 | GSE184899 | GEO
Project description:Adenosine deaminases acting on RNA (Adar1 and Adar2) catalyze I-to-A RNA editing, a post-transcriptional mechanism involved in multiple cellular functions. The role of Adar1-dependent RNA editing in cardiomyocytes (CMs) remains unclear. Here we show that conditional deletion of Adar1 in CMs results in myocarditis progressively evolving into dilated cardiomyopathy and heart failure at only 6 months of age. Adar1 depletion drives activation of interferon signaling genes (ISGs) in the absence of apoptosis and cytokine activation, and reduces the hypertrophic response of CMs upon pressure overload. Interestingly, ablation of the cytosolic sensor MDA5 prevents cardiac ISG activation and delays disease onset, but does not rescue the long-term lethal phenotype elicited by conditional deletion of Adar1. Retention of a single catalytically inactive Adar1 allele in CMs, in combination with MDA5 depletion, however, completely restores the cardiac function and prevents heart failure. Finally, ablation of interferon regulatory factor 7 (Irf7) attenuates the phenotype of Adar1-deficient CMs to a similar extent as MDA5 depletion, highlighting Irf7 as the main regulator of the immune response triggered by lack of Adar1 in CMs.
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