Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction

Pauw, Aurélia De; André, Emilie; Sekkali, Belaïd; Bouzin, Caroline; Esfahani, Hrag; Barbier, Nicolas; Loriot, Axelle; Smet, Charles De; Vanhoutte, Laetitia; Moniotte, Stéphane; Gerber, Bernhard; Mauro, Vittoria Di; Catalucci, Daniele; Feron, Olivier; Hilfiker‐Kleiner, Denise; Balligand, Jean‐Luc

doi:10.1172/jci.insight.91810

Cited by 12 publications

(11 citation statements)

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“…As freshly isolated CPC are generally a heterogenic pool of cells (22), two clonally expanded CPC cell lines (cCPC) (22, 32) were tested regarding their potential to differentiate into endothelial cells and adipocytes. We observed that the same passage of cCPC cell lines differentiate into endothelial cells on Matrigel (22, 32) or into adipocytes when adipocyte differentiation media and the peroxisome proliferator activated receptor γ (PPARγ) activator indomethacin (33) were added (S5A and S5B Figs). Adipocyte differentiation led to a reduction in SCA-1 and PDGFRα expression and an upregulation of the general adipocyte markers CEBPA and FABP4 (S5C–S5F Figs).…”

Section: Resultsmentioning

confidence: 99%

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Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Stelling

Ricke‐Hoch

Erschow

et al. 2020

Preprint

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31 Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline 32 with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency (CKO) 33 display premature age-related heart failure associated with reduced cardiac capillary density.34 In the present study isolated male and female CKO-cardiomyocytes exhibit increased 35 prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading 36 hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male 37 cardiomyocytes, which is associated with increased PGD 2 secretion from isolated male but not 38 female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from 39 impaired androgen-receptor-(AR)-signaling due to loss of its co-factor STAT3. Elevated PGD 2 40 secretion in males is associated with increased white adipocyte accumulation in aged male 41 but not female hearts. Adipocyte differentiation is enhanced in isolated SCA-1 + -cardiac-42 progenitor-cells (CPC) from young male CKO-mice compared to the adipocyte differentiation 43 of male wildtype (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly 44 isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and 45 hypomethylation in the white adipocyte differentiation gene Zfp423 associated with 46 upregulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation 47 compared to WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in 48 male CKO-CPC compared to male WT-CPC whereas no differences in the EZH2 expression 49 in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells 50 or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is 51 sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD 2 52 stimulation reduces the expression of EZH2 thereby upregulating ZFP423 expression and 53 promoting white adipocyte differentiation.54 Thus, cardiomyocyte STAT3-deficiency leads to age-related and sex-specific cardiac 55 remodeling and failure in part due to sex-specific alterations in PGD 2 secretion and subsequent 56 epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired 3 57 AR signaling in absence of STAT3, which reduces the expression of the PG degrading enzyme 58 HPGD. 59 4 60 Introduction 61 Men and women experience quite different cardiovascular disease susceptibility profiles and 62 outcome, a feature that is poorly understood. Further, the effects of biologic sex on health, 63 disease susceptibility and mortality are vastly understudied (1, 2). Recent studies showed that 64 genetics contribute to sex-specific differences in fat tissue and cardiovascular and metabolic 65 diseases (3). Pathophysiologically enhanced cardiac fat content is frequently observed in 66 patients with heart failure, in arrhythmogenic right ventricular dysplasia (ARVD), and after 67 ...

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Section: Resultsmentioning

confidence: 99%

“…SCA-1 + cell cloning was described previously (22, 32). The protocol for clonal expansion of CPC is given in the supplemental methods.…”

Section: Methodsmentioning

confidence: 99%

Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Stelling

Ricke‐Hoch

Erschow

et al. 2020

Preprint

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“…Although it becomes clearer that the beneficial effect of CPCs for cardiac function after infarction might be due to paracrine effects [23][24][25], it remains essential to study CPC metabolism to enhance their survival, proliferation and differentiation to improve therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Changes of Metabolic Phenotype of Cardiac Progenitor Cells During Differentiation: Neutral Effect of Stimulation of AMP-Activated Protein Kinase

André

Pauw

Verdoy

et al. 2019

Stem Cells and Development

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Cardiac progenitor cells (CPCs) in the adult mammalian heart, as well as exogenous CPCs injected at the border zone of infarcted tissue, display very low differentiation rate into cardiac myocytes and marginal repair capacity in the injured heart. Emerging evidence supports an obligatory metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) during stem cells differentiation, suggesting that pharmacological modulation of metabolism may improve CPC differentiation and, potentially, healing properties. In this study, we investigated the metabolic transition underlying CPC differentiation toward cardiac myocytes. In addition, we tested whether activators of adenosine monophosphate-activated protein kinase (AMPK), known to promote mitochondrial biogenesis in other cell types would also improve CPC differentiation. Stem cell antigen 1 (Sca1 +) CPCs were isolated from adult mouse hearts and their phenotype compared with more mature neonatal rat cardiac myocytes (NRCMs). Under normoxia, glucose consumption and lactate release were significantly higher in CPCs than in NRCMs. Both parameters were increased in hypoxia together with increased abundance of Glut1 (glucose transporter), of the monocarboxylic transporter Mct4 (lactate efflux mediator) and of Pfkfb3 (key regulator of glycolytic rate). CPC proliferation was critically dependent on glucose and glutamine availability in the media. Oxygen consumption analysis indicates that, compared with NRCMs, CPCs exhibited lower basal and maximal respirations with lower Tomm20 protein expression and mitochondrial DNA content. This CPC metabolic phenotype profoundly changed upon in vitro differentiation, with a decrease of glucose consumption and lactate release together with increased abundance of Tnnt2, Pgc-1a, Tomm20, and mitochondrial DNA content. Proliferative CPCs express both alpha1 and-2 catalytic subunits of AMPK that is activated by A769662. However, A769662 or resveratrol (an activator of Pgc-1a and AMPK) did not promote either mitochondrial biogenesis or CPC maturation during their differentiation. We conclude that although CPC differentiation is accompanied with an increase of mitochondrial oxidative metabolism, this is not potentiated by activation of AMPK in these cells.

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“…They have attracted more attention because of their capabilities of suppressing fibrosis and inflammation [17,18] and promoting angiogenesis [8,18]. Of note, exosomes are filled with various miRNAs that have been reported as powerful regulators of cellular effects and therapeutic targets [16,19–21]. Hence, it is of interest to identify myocardium-specific markers to isolate CSCs and study the possible mechanisms of their therapeutic efficacy.…”

Section: Cardiac Stem Cellsmentioning

confidence: 99%

“…It decreases Wif1 gene methylation by targeting Dnmt3a expression, which inhibits Wnt signaling and stimulates differentiation of Sca-1 + CSCs. Injection of CSCs with downregulated Dnmt3a in mouse hearts enhances CSC differentiation in situ and improves functional recovery of infarcted hearts [21]. Thus, miR-29a overexpression in infarcted myocardium has a great potential for increasing the differentiation capacity of endogenous CSCs, which could be used as a therapeutic opportunity.…”

Section: Mirna Signature and Function In Cardiac Stem Cellsmentioning

confidence: 99%

microRNAs and cardiac stem cells in heart development and disease

Meng

Zhang

2019

Drug Discovery Today

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Cumulative evidence has proven that proliferation, differentiation and migration of cardiac stem cells (CSCs) dominate early heart development and contribute to the later occurrence of heart disease. Among other mechanisms, microRNAs work as the 'fine-tuning' to modulate the levels of target genes in a specific cell type. The distinct microRNA signatures in CSCs reveal the stages and functions of CSCs. The focus of this review is to summarize recent knowledge advances in CSC proliferation, differentiation and migration and to discuss how microRNAs regulate these processes during heart development and in heart disease. Better understanding of microRNA regulation on CSCs under different situations will enable the unveiling of the mechanisms of heart disease and open new avenues in the therapeutic potentials of microRNA modulation to treat heart disease.

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Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction

Cited by 12 publications

References 54 publications

Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Changes of Metabolic Phenotype of Cardiac Progenitor Cells During Differentiation: Neutral Effect of Stimulation of AMP-Activated Protein Kinase

microRNAs and cardiac stem cells in heart development and disease

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Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction

Cited by 12 publications

References 54 publications

Increased prostaglandin-D2 in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Increased prostaglandin-D2 in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Changes of Metabolic Phenotype of Cardiac Progenitor Cells During Differentiation: Neutral Effect of Stimulation of AMP-Activated Protein Kinase

microRNAs and cardiac stem cells in heart development and disease

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Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation