Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158202 | GEO | 2022/03/01
REPOSITORIES: GEO
Similar Datasets
Project description:The immature phenotype of embryonic stem cell-derived cardiomyocytes (ESC-CMs) limits their application. However, the molecular mechanisms of cardiomyocyte maturation remain largely unexplored. This study found that overexpression of long noncoding RNA (lncRNA)-Cmarr, which was highly expressed in cardiomyocytes, promoted the maturation change and physiological maturation of mouse ESC-CMs (mESC-CMs). Moreover, transplantation of cardiac patch overexpressing Cmarr exhibited better retention of mESC-CMs, reduced infarct area by enhancing vascular density in the host heart, and improved cardiac function in mice after myocardial infarction. Mechanism studies identified that Cmarr acted as a competitive endogenous RNA to impede the repression of miR-540-3p on Dtna expression and promoted the binding of the dystrophin-glycoprotein complex (DGC) and yes-associated protein (YAP), which in turn reduced the proportion of nuclear YAP and the expression of YAP target genes. Therefore, this study revealed the function and mechanism of Cmarr in promoting cardiomyocyte maturation and provided a lncRNA that can be used as a functional factor in the construction of cardiac patches for the treatment of myocardial infarction.
| S-EPMC9382425 | biostudies-literature
Project description:Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression
| PRJNA664356 | ENA
Project description:Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of CM maturation which is subsequently required to generate adult myocytes, remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStatCM that indexes CM maturation status. MatStatCM reveals that pluripotent stem cell-derived CMs mature early in culture, but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.
2015-11-16 | GSE73233 | GEO
Project description:Contrary to adult mammals, zebrafish are able to regenerate their heart after cardiac injury. This regenerative response relies, in part, on the endogenous ability of cardiomyocytes (CMs) to dedifferentiate and proliferate to replenish the lost muscle. However, CM heterogeneity and population dynamics during development and regeneration remain poorly understood. Through comparative transcriptomic analyses of the developing and adult zebrafish heart, we identified tnnc2 and tnni4b.3 expression as markers for CMs at early and late developmental stages, respectively. Using newly developed reporter lines for these genes, we investigated their expression dynamics during development and regeneration, and observed interesting expression patterns. tnnc2 reporter lines label most CMs at embryonic stages, and this labeling declines rapidly during larval stages; in adult hearts expression is only detectable in a subset of CMs. Conversely, expression of a tnni4b.3 reporter is initially visible in outer curvature CMs at larval stages, and it is subsequently present in a vast majority of the CMs in adult hearts. Interestingly, we find that the adult CMs labeled by the embryonic reporter display higher levels of Tg(tp1:EGFP) expression, which indicates active Notch signaling. To further characterize this CM population, we performed transcriptomic analysis and found that it expresses genes encoding components of the Notch signaling pathway as well as markers of immature CMs. Moreover, during heart regeneration, proliferating CMs in the injured area activate the embryonic CM reporter. Overall, our findings provide further evidence of cardiomyocyte heterogeneity in the adult zebrafish heart.
2021-05-03 | GSE157662 | GEO
Project description:Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for the repair of the injured heart, but optimal cell production in a fully chemically defined and cost-effective system is essential for the efficacy and safety of cell transplantation therapies. In this study, we provided a simple and efficient strategy for cardiac differentiation from hPSCs and performed functional evaluation in a rat model of myocardial infarction. Using a chemically defined medium including four components, recombinant human albumin, ascorbic acid, human transferrin, and RPMI 1640, we developed a manageable and cost-effective protocol for robust generation of CMs from hPSCs. Interestingly, the addition of transferrin helped hPSCs to transit from TeSR-E8 medium to the simple cardiac differentiation medium and successfully initiated mesoderm differentiation without significant cell death. The CM generation efficiency was up to 85% based on cTnT expression. We performed transcriptome profiling from differentiation day 0 to 35, and characterized interesting dynamic change of cardiac genes. CMs derived from transferrin supplemented simple medium have similar transcriptome and the maturation level compared to cardiomyocytes generated in B27 minus insulin medium as well as their in vivo counterparts. Importantly, after transplantation, hPSC derived CMs survived in the infarcted rat heart, significantly improved the physiological function and reduced fibrosis. Our study offers an easy-to-use and cost-effective method for cardiac differentiation and facilitates the translational application of hPSC-derived CMs for heart repair.
2021-01-13 | GSE154294 | GEO
Project description:The mammalian adult heart is a post-mitotic organ characterized by mainly polyploid cardiomyocytes (CMs). The post-mitotic status of polyploid adult CMs poses a clear limit to heart regeneration. Thus, understanding how polyploid CMs acquire this status is relevant to heart regeneration therapies. Here, we aim to unveil whether the PIDDosome, a multi-protein complex known to limit scheduled and accidental polyploidization events by activating p53, implements a CM-specific genetic program that controls CM polyploidization during heart development. Flow cytometric DNA content analysis coupled with image-based 3D volumetric measurements of CM nuclei showed that PIDDosome knockout animals harbor significantly more polyploid CMs compared to WT animals. This increased CM ploidy levels do not interfere with both cardiac structure and functional output in steady-state and is a cell-autonomous phenotype. During heart development, ploidy analyses revealed that the PIDDosome starts to shape CM ploidy status at postnatal day 7 (P7), reaching a plateau of its action at P14. Moreover, PIDDosome activation in CM is dependent on PIDD1 localization to the extra mother centrioles via the distal appendage protein ANKRD26. Interestingly, in opposite to prior observations the PIDDosome limits CM polyploidization in a p53-independent manner that still involves p21, as confirmed in genetic and nuclear RNAseq analysis. Together these results identify a new molecular machinery that controls proliferation of polyploid CMs postnatally, adding a set of new players that control the tightly regulated program of the terminal CM differentiation occurring in the postnatal heart.
2026-01-20 | GSE275946 | GEO
Project description:The purpose of this study was to understand differences between maturation processes in endogenous and pluripotent stem cell-derived cardiomyocytes. To this end, we first expanded our previous reference of endogenous cardiomyocyte maturation, isolated by LP-FACS (see Kannan et al., bioRxiv 2020, and GSE147807). We subsequently generated PSCs from the same background strain and differentiated to CMs. CMs were isolated by conventional FACs.
2021-01-12 | GSE164591 | GEO
Project description:Mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. It has been shown that sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in cardiomyocytes and played an important role in heart development and pathological cardiac remodeling. Herein, we aim to investigate the role of CM-S1pr1 for cardiac regeneration and tissue repair after heart injury. We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and showed that CM-specific S1pr1 loss-of-function significantly severely reduced cardiomyocyte proliferation and heart regeneration in neonatal mice after both apex resection and myocardial infarction, whereas S1pr1 gain-of-function by AAV9-mediated CM-specific overexpression of S1pr1 significantly boosted cardiac regeneration and improved cardiac functions after heart injuries. We next identified that S1pr1 activated AKT/mTOR/CyclinD1 and Bcl-2 signaling pathways, and thus promoted cardiomyocyte proliferation and inhibited CM apoptosis, respectively.Of note, we applied CM-targeted gene therapy by AAV9-cTNT to specifically overexpress S1pr1 in cardiomyocytes and achieved an efficient S1pr1 overexpression in CMs in vivo. This CM-targeted strategy to overexpress S1pr1 significantly enhanced cardiac regeneration and improved cardiac functions after myocardial infarction in an adult mouse model, suggesting a potential strategy to boost adult cardiac regeneration in vivo.
2024-08-01 | GSE241722 | GEO
Project description:Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-induced pluripotent stem cells (iPSCs), day4 mesodermal cells, and day8, day20, and day30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day20 CMs was significantly higher compared to other cells. Transplantation of day20 CMs into the infarcted hearts of immunodeficient mice showed significant functional improvement. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. Differentiated cells, N=10 Undifferentiated pluripotent stem cells, N=1 Heart samples, N=6
2016-07-03 | E-GEOD-60634 | biostudies-arrayexpress
Project description:Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state.
2024-01-11 | GSE152856 | GEO