The Right Ventricular Fibroblast Secretome Drives Cardiomyocyte Dedifferentiation
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ABSTRACT:
PROVIDER: PRJNA552980 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: In virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We’ve previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells. Objective: To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. Methods and Results: Brief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. Conclusions: These data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.
2019-07-07 | GSE133904 | GEO
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| S-EPMC6677314 | biostudies-literature
Project description:Right ventricular failure was induced thourgh pulmonary banding in 11 pigs. Right ventricular failure was defined as a SRVP >50 mmHg during two hours. After right ventricular failure was induced, half the pigs were treatmed with a Glenn-shunt combined with pulmonary banding for one hour, and the other half served as control group with pulmonary banding only. The aim was to study the change in global gene expression during right ventricular failure due to pulmonary banding, and the effect of volume unloading during pulmonary banding. 11 pigs. Samples at the following time periods: 1) Baseline 2) Right ventricular failure 3) Treatment with modified Glenn-shunt/Control. After Right ventricular failure, pigs were divided into two groups a) Treatment with modified Glenn-shunt or b) Control group
2013-06-11 | E-GEOD-47814 | biostudies-arrayexpress
Project description:A porcine microarray study of acute right ventricular failure due to coronary artery ligation of the right ventricular free wall. 1. Baseline sample from the free right ventricular wall. 2. Ligation of the coronary arteries on the right ventricular free wall induced right ventricular heart failure. When the pressure in the right atrium rose to >20 mmHg, heart failure samples were taken from the free right ventricular wall.
2011-08-24 | GSE31619 | GEO
Project description:Right ventricular failure was induced thourgh pulmonary banding in 11 pigs. Right ventricular failure was defined as a SRVP >50 mmHg during two hours. After right ventricular failure was induced, half the pigs were treated with a Glenn-shunt combined with pulmonary banding for one hour, and the other half served as control group with pulmonary banding only. The aim was to study the change in global gene expression during right ventricular failure due to pulmonary banding, and the effect of volume unloading during pulmonary banding.
2013-06-11 | GSE47814 | GEO
Project description:A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle re-entry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. We also analyzed gene expression using data obtained from RNAseq of ventricular heart tissue from male and female mice subjected to either normoxia or hypoxia.
2023-02-15 | GSE221168 | GEO
Project description:Right ventricular (RV) failure plays a critical role in any type of heart failure. However, there is no specific therapy developed for RV failure. To understand RV failure, we focused on the RV specific genes. Global gene expression analysis showed that alternative complement pathway-related genes including C3 and Cfd were significantly upregulated in right ventricle in murine heart. We generated the RV failure by right ventricle-specific pressure overload model mice, pulmonary artery constriction (PAC), which induces RV failure around 14 days. After administration of C3a receptor (C3aR) antagonist, RV function was dramatically improved PAC-induced RV dysfunction in wild type mice. To investigate the role of C3a to cardiomyocyte, C3a recombinant protein was administerd to neonatal rat ventricular myocytes (NRVMs), the results that several MAP kinesis were phosphorylated by C3a. In turn, to identify the key expressed genes as downstream of C3a in NRVMs, global gene expression analysis was performed in vitro.
2021-09-07 | GSE183503 | GEO
Project description:Pressure overload greatly promotes neonatal right ventricular cardiomyocyte proliferation - a new model for heart regeneration study
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Project description:We reported the RNAseq analyses of right ventricualr free wall myocardium in neonatal volume overload (VO) SD rat. VO was induced by the fistula between abdominal aorta and inferior vena cava (AVF) within 24 hours postnatally (P1). RNAseq analyses of RV free wall at P7 from VO and sham-operated rat revealed that there were 454 differentially expressed genes between VO and sham group at P7. GO analysis showed that in the VO and sham comparison, the upregulated genes mainly mediated immune system response and the downregulated genes mainly mediated apoptotic process at P7. VO has no effect to neonatal right ventricular cardiomyocyte proliferation.
2021-12-08 | GSE180643 | GEO
Project description:We have demonstrated previously that adult cardiomyocytes can dedifferentiate and proliferate when cultured in vitro. To determine if cardiomyocyte dedifferentiation and cell cycling/proliferation happens in vivo, we applied here a novel multi-reporter transgenic mouse model (aMH-CMerCreMer;mT/MG;aMHC-H2BBFP) carrying reporter genes for permanent cardiomyocyte lineage mapping and maturity (dedifferentiation) reporting. With this new model, we deciphered the cellular sources and processes of cardiomyocyte dedifferentiation and proliferation in adult hearts. In this study, we used single-nucleus RNA-sequencing to tackle the challenges in analyzing the highly heterogeneous heart cell populations, and obtained datasets for a large number of cardiac single nuclei (both myocytes and non-myocytes) for control and post-infarct hearts. We identified specific cell populations in the heart using distinct transcriptomic clusters, transgenic reporters for ACM lineage and dedifferentiation, as well as cell cycle markers. The results demonstrated that the dedifferentiation and cell cycle progression of pre-existing CMs was augmented in post-infarct hearts, with a number of signaling pathways and gene sets affected. This is the first study dissecting the transcriptomic profiles and signaling pathways associated with cardiomyocyte dedifferentiation and cycling/proliferation in vivo using unbiased high-throughput single-nucleus RNA-Seq analysis, in junction with novel cell lineage (e.g. cardiomyocyte) and phenotyping (e.g. dedifferentiation) transgenic model systems.
2019-07-02 | GSE128628 | GEO