Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1313185 | ENA |
REPOSITORIES: ENA
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Project description:Mutations in the Hsp70 co-chaperone Bcl2-associated athanogene 3 (Bag3) result in myofibrillar myopathy and pediatric hypertrophic cardiomyopathy (pHCM) in human patients, but the pathological mechanisms underlying Bag3 dysfunction in the developing heart have remained unclear. Here we show that conditional ablation of Bag3 in cardiomyocytes (CMs) results in progressive cardiomyopathy accompanied by increased autophagic flux and autophagosome accumulation in the early post-natal period. Autophagy inhibition via acute administration of chloroquine (CQ) results in transient accumulation of cardiac proteins in the detergent-insoluble fraction, implying a role for autophagy in the degradation of unfolded proteins in the absence of Bag3 co-chaperone activity. Exacerbated autophagy in Bag3 deficient CMs leads to decreased soluble levels of proteins involved in cardiac contraction and conduction, including the gap junction protein connexin 43 (Cx43). Importantly, chronic CQ treatment during the early post-natal period results in a significant amelioration of the pathological phenotype, with recovered contractile performances and restoration of soluble levels of autophagy-targeted proteins. We therefore conclude that loss of Bag3 in CMs leads to autophagic flux exacerbation and that CQ treatment is relevant to therapeutic strategies for Bag3-dependent pHCM patients.
2024-06-05 | PXD016095 | Pride
Project description:Analysis of differential gene expression in Human endometrial endothelial cells (HEECs) incubated with CMS derived from human endoemtrial stromal cells (HESCs) treated by LAPCs. We tested the hypothesis that paracrine factors sectreted from HESCs treated LAPCs, etonogestrol (ETO) or medorxyprogesterone acetate (M) influence several common genes associated with survival in HEECs. Thefore, whole genome analyses were performed in HEECs treated with HESC derived CMS obtained from vehicle (estrodial (E) as control) or progesterone (P) or ETO or M incubations under hypoxia (HX) and normoxia (NX). Results provide important information of several common and unique gene expression profiles in cultured HEECs treated with HESC CMS from P or ETO or M incubations. Among M and ETO responsive genes, up- or down-regulated survival related common genes were determined and used further confirmation and in vitro functional analyses. Total RNA (n=3) obtained from cultured HEECs incubated 6h with vehicle- or P4- or ETO- or MPA- treated NX or HX conditioned HESC-derived CMS.
2014-03-08 | E-GEOD-55691 | biostudies-arrayexpress
Project description:Prior work suggests that exercise-responsive molecules may mediate exercise-induced myocardial physiological growth and promote functional recovery after ischemia- reperfusion injury in adult mice. Based on these findings, multiple mouse models of myocardial physiological growth have been successfully established. However, an in vitro model of physiological growth in cardiomyocytes derived from human embryonic stem cells (hESC-CMs) has not been successfully developed. To address this gap, we generated an inducible hESC cell line with forced Cbp/P300 Interacting Transactivator with Glu/Asp Rich Carboxy-Terminal Domain 4 (CITED4) gene expression, and differentiated those hESCs towards cardiomyocytes. The results showed that CITED4 expression increased cell size and proliferation in hESC-CMs, and promoted cardiomyocyte proliferation in 3D cardiac microtissues. Forced expression of CITED4 induced activation of Protein kinase B (also known as AKT1) signaling, which was necessary for CITED4-induced proliferation of hESC-CMs and 3D cardiac microtissues, while mTOR signaling mediated both proliferation and physiological hypertrophy induced by CITED4. In an in vitro model mimicking ischemia-reperfusion, CITED4 expression inhibited cardiomyocyte apoptosis in hESC-CMs and 3D cardiac microtissues, and this effect was mediated by activation of mTOR signaling. In conclusion, we successfully generate a physiological growth model in hESC-CMs and 3D cardiac microtissues. Moreover, physiological growth induced by CITED4 is mediated by activation of the mTOR signaling, which is necessary to promote proliferation and physiological hypertrophy, and to alleviate apoptosis after ischemia- reperfusion injury in hESC-CMs and 3D cardiac microtissues.
2025-12-03 | GSE294627 | GEO
Project description:Absence of the dystrophin gene in Duchenne muscular dystrophy (DMD) results in the degeneration of skeletal and cardiac muscles. Owing to advances in respiratory medicine, cardiomyopathy has become a significant aspect of the disease. While CRISPR/Cas9 genome editing technology holds great potential as a novel therapeutic avenue for DMD, little is known about the efficacy of correction of DMD using the CRISPR/Cas9 system in mitigating the cardiomyopathy phenotype in DMD. To define the effects of CRISPR/Cas9 genome editing on structural, functional and transcriptional dysregulation in DMD-associated cardiomyopathy. We generated induced pluripotent stem cells (iPSCs) from a patient with a deletion of exon 44 of the DMD gene (ΔEx44) and his healthy brother. Here, we targeted exon 45 of the DMD gene by CRISPR/Cas9 genome editing to generate corrected DMD (cDMD) iPSC lines, wherein the DMD open reading frame was restored via reframing (RF) or exon skipping (ES). While DMD cardiomyocytes (CMs) demonstrated morphologic, structural and functional deficits compared to control CMs, CMs from both cDMD lines were similar to control CMs. Bulk RNA-sequencing of DMD CMs showed transcriptional dysregulation consistent with dilated cardiomyopathy, which was mitigated in cDMD CMs. We then corrected DMD CMs by adenoviral delivery of Cas9/gRNA and showed that postnatal correction of DMD CMs reduces their arrhythmogenic potential. Single-nucleus RNA-sequencing of hearts showed reduced transcriptional dysregulation in CMs and fibroblasts in corrected mice compared with DMD mice, consistent with reduced histopathologic changes.We show that CRISPR/Cas9-mediated correction of DMD ΔEx44 mitigates structural, functional and transcriptional dysregulation consistent with dilated cardiomyopathy irrespective of how the protein reading frame is restored. We show that these effects extend to postnatal editing in iPSC-CMs and mice. These findings provide key insights into the utility of genome editing as a novel therapeutic for DMD-associated cardiomyopathy.
2021-08-02 | GSE169551 | GEO
Project description:Phospholamban R14del mutazion (PLN-R14del) has been identified in a large family pedigree in which heterozygous carriers exhibited inherited dilated cardiomyopathy (DCM) and death by middle age. To better understand the causal link between the mutations in PLN and DCM pathology, we derived induced pluripotent stem cells from a DCM patient carrying the PLN R14del mutation. We showed that iPSC-derived cardiomyocytes recapitulated the DCM-specific phenotype and demonstrated that either TALEN-mediated genetic correction or combinatorial gene therapy resulted in phenotypic rescue. Our findings offer novel insights into the pathogenesis caused by mutant PLN and point to the development of potential new therapeutics of pathogenic genetic variants associated with inherited cardiomyopathies. Submitter confirms there are no patient privacy concerns with these data. iPSCs were derived from a female patient carrying a heterozygous mutation (R14del) in the PLN gene. Tree samples were analyzed: R14del-CMs (clone L2), corrected R14del-CMs (clone L2GC1) and corrected R14del-CMs (clone L2GC2)
2015-02-09 | E-GEOD-65762 | biostudies-arrayexpress
Project description:Rationale – Absence of the dystrophin gene in Duchenne muscular dystrophy (DMD) results in the degeneration of skeletal and cardiac muscles. Owing to advances in respiratory medicine, cardiomyopathy has become a significant aspect of the disease. While CRISPR/Cas9 genome editing technology holds great potential as a novel therapeutic avenue for DMD, little is known about the efficacy of correction of DMD using the CRISPR/Cas9 system in mitigating the cardiomyopathy phenotype in DMD. Objective – To define the effects of CRISPR/Cas9 genome editing on structural, functional and transcriptional dysregulation in DMD-associated cardiomyopathy. Methods and Results – We generated induced pluripotent stem cells (iPSCs) from a patient with a deletion of exon 44 of the DMD gene (ΔEx44) and his healthy brother. Here, we targeted exon 45 of the DMD gene by CRISPR/Cas9 genome editing to generate corrected DMD (cDMD) iPSC lines, wherein the DMD open reading frame was restored via reframing (RF) or exon skipping (ES). While DMD cardiomyocytes (CMs) demonstrated morphologic, structural and functional deficits compared to control CMs, CMs from both cDMD lines were similar to control CMs. Bulk RNA-sequencing of DMD CMs showed transcriptional dysregulation consistent with dilated cardiomyopathy, which was mitigated in cDMD CMs. We then corrected DMD CMs by adenoviral delivery of Cas9/gRNA and showed that postnatal correction of DMD CMs reduces their arrhythmogenic potential. Single-nucleus RNA-sequencing of hearts showed reduced transcriptional dysregulation in CMs and fibroblasts in corrected mice compared with DMD mice, consistent with reduced histopathologic changes. Conclusions – We show that CRISPR/Cas9-mediated correction of DMD ΔEx44 mitigates structural, functional and transcriptional dysregulation consistent with dilated cardiomyopathy irrespective of how the protein reading frame is restored. We show that these effects extend to postnatal editing in iPSC-CMs and mice. These findings provide key insights into the utility of genome editing as a novel therapeutic for DMD-associated cardiomyopathy.
2021-08-06 | GSE169190 | GEO
Project description:hPSC-CMs resemble immature embryonic or fetal CMs rather than mature adult CMs, and have limitations in disease modeling and pharmacological studies. Therefore, hPSCs-derived mature and ventricular CMs are required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. FGF4+AA-treated hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes related to cellular responses to glycolytic processes, oxygen levels, HIF-1 signaling, apoptotic processes, and regulation of cell death including potential cardiac biomarkers proved in clinical studies in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated hESC-CMs in response to hypoxia based on transcriptome analyses.
2021-04-11 | GSE171824 | GEO
Project description:Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal step-wise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins.
2023-10-24 | PXD042075 | Pride