Proliferation Of Cardiac Progenitor Cells Research Articles

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review

BackgroundCardiac Myxoma is a primary tumor of heart. Its origins, rarity of the occurrence of primary cardiac tumors and how it may be related to limited cardiac regenerative potential, are not yet entirely known. This study investigates the key cardiac genes/ transcription factors (TFs) and signaling pathways to understand these important questions.MethodsDatabases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving cardiac myxoma, cardiac genes/TFs/signaling pathways and their roles in cardiogenesis, proliferation, differentiation, key interactions and tumorigenesis, with focus on cardiomyocytes.ResultsThe cardiac genetic landscape is governed by a very tight control between proliferation and differentiation-related genes/TFs/pathways. Cardiac myxoma originates possibly as a consequence of dysregulations in the gene expression of differentiation regulators including Tbx5, GATA4, HAND1/2, MYOCD, HOPX, BMPs. Such dysregulations switch the expression of cardiomyocytes into progenitor-like state in cardiac myxoma development by dysregulating Isl1, Baf60 complex, Wnt, FGF, Notch, Mef2c and others.The Nkx2–5 and MSX2 contribute predominantly to both proliferation and differentiation of Cardiac Progenitor Cells (CPCs), may possibly serve roles based on the microenvironment and the direction of cell circuitry in cardiac tumorigenesis. The Nkx2–5 in cardiac myxoma may serve to limit progression of tumorigenesis as it has massive control over the proliferation of CPCs. The cardiac cell type-specific genetic programming plays governing role in controlling the tumorigenesis and regenerative potential.ConclusionThe cardiomyocytes have very limited proliferative and regenerative potential. They survive for long periods of time and tightly maintain the gene expression of differentiation genes such as Tbx5, GATA4 that interact with tumor suppressors (TS) and exert TS like effect. The total effect such gene expression exerts is responsible for the rare occurrence and benign nature of primary cardiac tumors. This prevents the progression of tumorigenesis. But this also limits the regenerative and proliferative potential of cardiomyocytes. Cardiac Myxoma develops as a consequence of dysregulations in these key genes which revert the cells towards progenitor-like state, hallmark of CM. The CM development in carney complex also signifies the role of TS in cardiac cells.

PiRNA in Cardiovascular Disease: Focus on Cardiac Remodeling and Cardiac Protection.

Cardiovascular diseases (CVDs) are common causes of death, which take about 18.6 million lives worldwide every year. Currently, exploring strategies that delay ventricular remodeling, reduce cardiomyocyte death, and promote cardiomyocyte regeneration has been the hotspot and difficulty of the ischemic heart disease (IHD) research field. Previous studies indicate that piwi-interacting RNA (piRNA) plays a vital role in the occurrence and development of cardiac remodeling and may offer novel therapeutic strategies for cardiac repair. The best-known biological function of piRNA is to silence transposons in cells. In the cardiovascular system, piRNA is known to participate in cardiac progenitor cell proliferation, AKT pathway regulation, and cardiac remodeling and decompensation. In this review, we systematically discuss the research progress on piRNA in CVDs, especially the mechanism of cardiac remodeling and the potential functions in cardiac protection, which provides new insights for the progress and treatment of cardiovascular diseases. Piwi-interacting RNA (piRNA) is one of the noncoding RNAs, with the best -known biological function to silence transposons in cells. Now piRNA is found to participate in cardiac progenitor cell proliferation, AKT pathway regulation, cardiac remodeling and decompensation, which implies the potential of piRNA in the diagnosis and treatment of cardiovascular diseases. Over expression of piRNA could promote cardiac apoptosis and cardiac hypertrophy, thus targeted therapy which inhibits expression of associated piRNA may reduce cardiac remodeling and reduce inflammation caused by necrotic cardiomyocytes. PiRNA is also speculated to participate in the proliferation of cardiac progenitor cells, implying the potential to induce cardiac regeneration th erapy, which provides new insights for treatment of cardiovascular diseases. At present, the treatment strategy of cardiac remodeling emphasizes the control of risk factors, prevention of disease progression and individualized treatment. With further studies in mechanism of piRNA, potential therapies above may come true and more therapies in cardiovascular diseases may be found.

Induction of Stem-Cell-Derived Cardiomyogenesis by Fibroblast Growth Factor 10 (FGF10) and Its Interplay with Cardiotrophin-1 (CT-1)

Simple SummaryCardiovascular diseases are worldwide one of the leading contributors of mortality, and among multiple therapeutic approaches, stem cell therapy has been introduced as a robust therapeutic strategy to alleviate related symptoms and restore cardiac functions. Prior to this, however, for successful cell therapy, an adequate number of functional and safe cardiac cells needs to be generated. For this purpose, our approach was boosting the proliferative capacity of stem cell-derived cardiomyocytes using growth factors, such as fibroblast growth factor 10 (FGF10) and cardiotrophin-1 (CT-1). Our results demonstrated that FGF10 and CT-1 substantially increased the number of cardiac cells that originated from stem cells. In molecular assays, to assess RNA and protein level alterations, the enhanced presence of specific markers for cardiac cells after treatment of stem cells with FGF10 and/or CT-1 was confirmed. This inducing potential of cardiac cells can particularly be applicable in the cell replacement-based therapies of cardiac infarction. This research sheds light on the putative effect of FGF10 and CT-1 in the transition of stem cells to cardiac cells, leading to the repair and survival of the heart.For heart regeneration purposes, embryonic stem cell (ES)-based strategies have been developed to induce the proliferation of cardiac progenitor cells towards cardiomyocytes. Fibroblast growth factor 10 (FGF10) contributes to cardiac development and induces cardiomyocyte differentiation in vitro. Yet, among pro-cardiogenic factors, including cardiotrophin-1 (CT-1), the hyperplastic function of FGF10 in cardiomyocyte turnover remains to be further characterized. We investigated the proliferative effects of FGF10 on ES-derived cardiac progenitor cells in the intermediate developmental stage and examined the putative interplay between FGF10 and CT-1 in cardiomyocyte proliferation. Mouse ES cells were treated with FGF10 and/or CT-1. Differential expression of cardiomyocyte-specific gene markers was analyzed at transcript and protein levels. Substantial upregulation of sarcomeric α-actinin was detected by qPCR, flow cytometry, Western blot and immunocytochemistry. FGF10 enhanced the expression of other structural proteins (MLC-2a, MLC-2v and TNNT2), transcriptional factors (NKX2-5 and GATA4), and proliferation markers (Aurora B and YAP-1). FGF10/CT-1 co-administration led to an upregulation of proliferation markers, suggesting the synergistic potential of FGF10 + CT-1 on cardiomyogenesis. In summary, we provided evidence that FGF10 and CT-1 induce cardiomyocyte structural proteins, associated transcription factors, and cardiac cell proliferation, which could be applicable in therapies to replenish damaged cardiomyocytes.

Cardiomyocyte-GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms.

Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here, we sought to identify the potential roles of glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation post-myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension and contractile functions were comparable at 2 weeks post-MI, cKO mice displayed significantly preserved LV chamber and contractile function versus control mice at 4 weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit-positive cells (KPCs) were observed in the cKO hearts at 4 and 6 weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage, as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression and secretion of growth factors, including basic-fibroblast growth factor, angiopoietin-2, erythropoietin, stem cell factor, platelet-derived growth factor-BB, granulocyte colony-stimulating factor, and vascular endothelial growth factor, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocyte and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte-GSK-3β could be helpful for the promotion of in situ cardiac regeneration post-ischemic injury.

Abstract P409: GSK-3β Deficiency In Cardiomyocyte Induces Cardiac Progenitor Cell Proliferation In The Ischemic Heart

The cardiomyocytes are terminally differentiated cells and ischemia-induced cardiomyopathy is an irreparable loss. Novel strategies are needed to induce resident cardiac progenitor cells (CPCs) proliferation in situ to enhance the possibility of cardiac regeneration. Here we sought to identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPCs proliferation in the ischemic heart. Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were recruited and challenged with myocardial infarction (MI). The cardiac function was assessed using trans-thoracic M-mode echocardiography. The level of CPC proliferation in the ischemic cKO hearts was determined at 2, 4 and 8 weeks post-MI through immunofluorescence labeling of stem cell marker c-Kit. To confirm the lineage of identified c-Kit -positive cells (KPCs) in the heart, a hematopoietic lineage marker was stained along with c-Kit. The cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable until 2 weeks post-MI. The cKO mice displayed significantly preserved LV chamber [LVIDd(mm); 5.01±0.67 vs.6.09±0.65, p =0.01] and contractile function [LVEF(%); 31.98±8.52 vs. 18.06±7.11., p =0.01] in comparison to control mice at 4 week post-MI. Consistent with protective phenotypes, an increased percentage of KPC was observed in the cKO hearts at 4 and 6-weeks post-MI which was accompanied by an increased level of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts were mostly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic marker, CD45. In conclusion, our findings strongly suggest that GSK-3β inhibits CPCc proliferation post-ischemia, and loss of GSK-3β in cardiomyocytes promotes resident CPCc proliferation potentially through paracrine mechanisms.

Bioinspired Device Improves The Cardiogenic Potential of Cardiac Progenitor Cells.

Objective Functional cardiac tissue engineering holds promise as a candidate approach for myocardial infarction. Tissue engineering has emerged to generate functional tissue constructs and provide an alternative means to repair and regenerate damaged heart tissues. Materials and Methods In this experimental study, we fabricated a composite polycaprolactone (PCL)/gelatine electrospun scaffold with aligned nanofibres. The electrospinning parameters and optimum proportion of the PCL/ gelatine were tested to design a scaffold with aligned and homogenized nanofibres. Using scanning electron microscopy (SEM) and mechanophysical testes, the PCL/gelatine composite scaffold with a ratio of 70:30 was selected. In order to simulate cardiac contraction, a developed mechanical loading device (MLD) was used to apply a mechanical stress with specific frequency and tensile rate to cardiac progenitor cells (CPCs) in the direction of the aligned nanofibres. Cell metabolic determination of CPCs was performed using real-time polymerase chain reaction(RT-PCR). Results Physicochemical and mechanical characterization showed that the PCL/gelatine composite scaffold with a ratio of 70:30 was the best sample. In vitro analysis showed that the scaffold supported active metabolism and proliferation of CPCs, and the generation of uniform cellular constructs after five days. Real-time PCR analysis revealed elevated expressions of the specific genes for synchronizing beating cells (MYH-6, TTN and CX-43) on the dynamic scaffolds compared to the control sample with a static culture system. ConclusionOur study provides a robust platform for generation of synchronized beating cells on a nanofibre patch that can be used in cardiac tissue engineering applications in the near future.

Isolation, growth kinetics, and immunophenotypic characterization of adult human cardiac progenitor cells.

The discovery of cardiac progenitor cells (CPCs) has raised expectations for the development of cell-based therapy of the heart.Although cell therapy is emerging as a novel treatment for heart failure, several issues still exist concerning an unambiguous definition of the phenotype of CPC types. There is a need to define and validate the methods for the generation of quality CPC populations used in cell therapy applications. Considering the critical roles of cardiac cell progenitors in cellular therapy, we speculate that long term culture might modulate the immunophenotypes of CPCs. Hence, a strategy to validate the isolation and cell culture expansion of cardiac cell populations was devised. Isolation of three subpopulations of human CPCs was done from a single tissue sample using explant, enzymatic isolation, and c-kit+ immunomagnetic sorting methods. The study assessed the effects of ex vivo expansion on proliferation, immunophenotypes, and differentiation of CPCs. Additionally, we report that an explant culture can take over 2 months to achieve similar cell yields, and cell sorting requires a much larger starting population to match this expansion time frame. In comparison, an enzymatic method is expected to yield equivalent quantities of CPCs in 2-3 weeks, notably at a significantly lower cost, which may intensify their use in therapeutic approaches. We determined that ex vivo expansion caused changes in cellular characteristics, and hence propose validated molecular signatures should be established to evaluate the impact of ex vivo expansion for a safe cell therapy product.

LncRNA CRNDE modulates cardiac progenitor cells' proliferation and migration via the miR-181a/LYRM1 axis in hypoxia.

BackgroundThe cardiac progenitor cells provide a valuable method for myocardial infarction related heart failure therapies. But cardiac progenitor cell quickly loses the proliferation abilities during the myocardial infarction. In this paper, we aim to explore the role of lncRNA CRNDE in the modulation of cardiac progenitor cell reproduction and migration.MethodsCardiac progenitor cells were isolated from neonatal adult Sprague-Dawley rats by removing the heart and homogenizing the tissue. Various siRNAs and RNA mimics were co-transfected to the cells. A list of characterization methods, including qRT-PCR, Western blotting, luciferase assay, CCK-8 assay, and EdU incorporation assay, were utilized to verify the roles and interactions of CRNDE, miR-181a, and LYRM1 in cardiac progenitor cells’ proliferation and migration potentials.ResultsLncRNA CRNDE expressions were substantially promoted in the CoCl2-related hypoxia cardiac progenitor cell model. CRNDE suppression inhibited cardiac progenitor cell reproduction and migration under hypoxic conditions. The miR-181a-inhibitor restored the reproduction and migration potentials of cardiac progenitor cells after CRNDE knockdown in hypoxia. LYR motif containing 1 (LYRM1) was a target of miR-181a, and miR-181a negatively modulated its expressions. LYRM1 knockdowns inhibited miR-181a-inhibitor's protective effects for cardiac progenitor cell functions in hypoxia.ConclusionsOur experiments and analysis demonstrated that CRNDE could modulate cardiac progenitor cell proliferation and migration potentials via the miR-181a/LYRM1 axis in hypoxia.

Fetal Hypoxia Impacts on Proliferation and Differentiation of Sca-1+ Cardiac Progenitor Cells and Maturation of Cardiomyocytes: A Role of MicroRNA-210.

Hypoxia is one of the most frequent and severe stresses to an organism’s homeostatic mechanisms, and hypoxia during gestation has profound adverse effects on the heart development increasing the occurrence of congenital heart defects (CHDs). Cardiac progenitor cells (CPCs) are responsible for early heart development and the later occurrence of heart disease. However, the mechanism of how hypoxic stress affects CPC fate decisions and contributes to CHDs remains a topic of debate. Here we examined the effect of hypoxic stress on the regulations of CPC fate decisions and the potential mechanism. We found that experimental induction of hypoxic responses compromised CPC function by regulating CPC proliferation and differentiation and restraining cardiomyocyte maturation. In addition, echocardiography indicated that fetal hypoxia reduced interventricular septum thickness at diastole and the ejection time, but increased the heart rate, in mouse young adult offspring with a gender-related difference. Further study revealed that hypoxia upregulated microRNA-210 expression in Sca-1+ CPCs and impeded the cell differentiation. Blockage of microRNA-210 with LNA-anti-microRNA-210 significantly promoted differentiation of Sca-1+ CPCs into cardiomyocytes. Thus, the present findings provide clear evidence that hypoxia alters CPC fate decisions and reveal a novel mechanism of microRNA-210 in the hypoxic effect, raising the possibility of microRNA-210 as a potential therapeutic target for heart disease.

P2X5 purinergic receptor: A novel regulator of human cardiac progenitor cell proliferation and survival

P2X5 purinergic receptor: A novel regulator of human cardiac progenitor cell proliferation and survival

Phenotypic Screen with the Human Secretome Identifies FGF16 as Inducing Proliferation of iPSC-Derived Cardiac Progenitor Cells.

Paracrine factors can induce cardiac regeneration and repair post myocardial infarction by stimulating proliferation of cardiac cells and inducing the anti-fibrotic, antiapoptotic, and immunomodulatory effects of angiogenesis. Here, we screened a human secretome library, consisting of 923 growth factors, cytokines, and proteins with unknown function, in a phenotypic screen with human cardiac progenitor cells. The primary readout in the screen was proliferation measured by nuclear count. From this screen, we identified FGF1, FGF4, FGF9, FGF16, FGF18, and seven additional proteins that induce proliferation of cardiac progenitor cells. FGF9 and FGF16 belong to the same FGF subfamily, share high sequence identity, and are described to have similar receptor preferences. Interestingly, FGF16 was shown to be specific for proliferation of cardiac progenitor cells, whereas FGF9 also proliferated human cardiac fibroblasts. Biosensor analysis of receptor preferences and quantification of receptor abundances suggested that FGF16 and FGF9 bind to different FGF receptors on the cardiac progenitor cells and cardiac fibroblasts. FGF16 also proliferated naïve cardiac progenitor cells isolated from mouse heart and human cardiomyocytes derived from induced pluripotent cells. Taken together, the data suggest that FGF16 could be a suitable paracrine factor to induce cardiac regeneration and repair.

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

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-1α, 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-1α 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.

Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach.

Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post‐MI cardiac dysfunction. We have used an in vitro human induced pluripotent stem cell‐derived CPC model to screen a 10,000‐compound library containing molecules representing different target classes and compounds reported to modulate the phenotype of stem or primary cells. The primary readout of this phenotypic screen was proliferation as measured by nuclear count. We identified retinoic acid receptor (RAR) agonists as potent proliferators of CPCs. The CPCs retained their progenitor phenotype following proliferation and the identified RAR agonists did not proliferate human cardiac fibroblasts, the major cell type in the heart. In addition, the RAR agonists were able to proliferate an independent source of CPCs, HuES6. The RAR agonists had a time‐of‐differentiation‐dependent effect on the HuES6‐derived CPCs. At 4 days of differentiation, treatment with retinoic acid induced differentiation of the CPCs to atrial cells. However, after 5 days of differentiation treatment with RAR agonists led to an inhibition of terminal differentiation to cardiomyocytes and enhanced the proliferation of the cells. RAR agonists, at least transiently, enhance the proliferation of human CPCs, at the expense of terminal cardiac differentiation. How this mechanism translates in vivo to activate endogenous CPCs and whether enhancing proliferation of these rare progenitor cells is sufficient to enhance cardiac repair remains to be investigated.

Insulin-like growth factor-1 short-period therapy improves cardiomyopathy stimulating cardiac progenitor cells survival in obese mice

Background and aimsCardiovascular diseases are the main cause of mortality in obesity. Despite advanced understanding, the mechanisms that regulate cardiac progenitor cells (CPC) survival in pathological conditions are not clear. Low IGF-1 plasma levels are correlated to obesity, cardiomyopathy and CPC death, so this work aimed to investigate IGF-1 therapeutic potential on cardiomyopathy and its relationship with the survival, proliferation and differentiation of CPC in Western diet-induced obesity. Methods and resultsMale Swiss mice were divided into control group (CG, n = 8), fed with standard diet; and obese group (OG, n = 16), fed with Western diet, for 12 weeks. At 11th week, OG was subdivided to receive a daily subcutaneous injection of human recombinant IGF-1 (100 μg.Kg−1) for seven consecutive days (OG + IGF1, n = 8). Results showed that IGF-1 therapy improved the metabolic parameters negatively impacted by western diet in OG, reaching levels similar to CG. OG + IGF-1 also demonstrated restored heart energetic metabolism, fibrosis resolution, decreased apoptosis level, restored cardiac gap junctions and intracellular calcium balance. Cardiomyopathy improvement was accompanied by increased CPC survival, proliferation and newly cardiomyocytes formation related to increased pAkt/Akt ratio. ConclusionThese results suggest that only one week of IGF-1 therapy has cardioprotective effects through Akt pathway upregulation, ensuring CPC survival and differentiation, contributing to heart failure rescue.

Trim33 is required for appropriate development of pre-cardiogenic mesoderm

Congenital cardiac malformations are among the most common birth defects in humans. Here we show that Trim33, a member of the Tif1 subfamily of tripartite domain containing transcriptional cofactors, is required for appropriate differentiation of the pre-cardiogenic mesoderm during a narrow time window in late gastrulation. While mesoderm-specific Trim33 mutants did not display noticeable phenotypes, epiblast-specific Trim33 mutant embryos developed ventricular septal defects, showed sparse trabeculation and abnormally thin compact myocardium, and died as a result of cardiac failure during late gestation. Differentiating embryoid bodies deficient in Trim33 showed an enrichment of gene sets associated with cardiac differentiation and contractility, while the total number of cardiac precursor cells was reduced. Concordantly, cardiac progenitor cell proliferation was reduced in Trim33-deficient embryos. ChIP-Seq performed using antibodies against Trim33 in differentiating embryoid bodies revealed more than 4000 peaks, which were significantly enriched close to genes implicated in stem cell maintenance and mesoderm development. Nearly half of the Trim33 peaks overlapped with binding sites of the Ctcf insulator protein. Our results suggest that Trim33 is required for appropriate differentiation of precardiogenic mesoderm during late gastrulation and that it will likely mediate some of its functions via multi-protein complexes, many of which include the chromatin architectural and insulator protein Ctcf.

Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia-reperfusion injury.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-β1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-β signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-β signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.

Atorvastatin protects cardiac progenitor cells from hypoxia-induced cell growth inhibition via MEG3/miR-22/HMGB1 pathway.

Heart failure (HF) induced by ischemia myocardial infarction (MI) is one of the major causes of morbidity and mortality all around the world. Atorvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, has been demonstrated to benefit patients with ischemic or non-ischemic-induced HF, but the mechanism is still poorly understood. Increasing evidence indicates that lncRNAs play important role in variety of human disease. However, the role and underlying molecular mechanisms remain largely unclear. In our work, we applied 0.5% O2 to generate a hypoxia cardiac progenitor cell (CPC) model. Then, CCK8 and EdU assays were employed to investigate the role of atorvastatin in hypoxia CPC cell model. We found that hypoxia inhibits CPC viability and proliferation through modulating MEG3 expression, while atorvastatin application can protect CPCs from hypoxia-induced injury through inhibiting MEG3 expression. Then, we demonstrated that repression of MEG3 inhibited the hypoxia-induced injury of CPCs and overexpression of MEG3 inhibited the protective effect of atorvastatin in the hypoxia-induced injury of CPCs. Furthermore, our study illustrated that atorvastatin played its role in CPC viability and proliferation by modulating the expression of HMGB1 through the MEG3/miR-22 pathway. Our study, for the first time, uncovered the molecular mechanism of atorvastatin's protective role in cardiomyocytes under hypoxia condition, which may provide an exploitable target in developing effective therapy drugs for MI patients.

Hypoxia induces hypomethylation of the HMGB1 promoter via the MAPK/DNMT1/HMGB1 pathway in cardiac progenitor cells.

Apoptosis is involved in the death of cardiac progenitor cells (CPCs) after myocardial infarction (MI) in the heart. The loss of CPCs results in infarct scar and further deterioration of the heart function. Though stem cell-based therapy provides an effective approach for heart function recovery after MI, the retention of CPCs in the infarcted area of the heart is the main barrier that limits its promising therapy. Therefore, the underlying mechanisms of CPC apoptosis in hypoxia are important for the development of new therapeutic targets for MI patients. In this work, we found that the expression of high-mobility group box 1(HMGB1) was upregulated in CPCs under hypoxia conditions. Further study demonstrated that HMGB1 was regulated by DNA methyltransferases 1 (DNMT1) via changing the methylation state of CpGs in the promoter of HMGB1 in CPCs during hypoxia process. Additionally, mitogen-activated protein kinase (MAPK) signaling pathway was found to be involved in regulating DNMT1/HMGB1-mediated CPC apoptosis in hypoxia process. In conclusion, our findings demonstrate a novel regulatory mechanism for CPC apoptosis and proliferation under hypoxia conditions, which may provide a new therapeutic approach for MI patients.

Long non-coding RNA H19 contributes to hypoxia-induced CPC injury by suppressing Sirt1 through miR-200a-3p.

Cardiomyocyte death is the chief obstacle that prevents the heart function recovery in myocardial infarction (MI)-induced heart failure (HF). Cardiac progenitor cells (CPCs)-based myocardial regeneration has provided a promising method for heart function recovery after MI. However, CPCs can easily lose their proliferation ability due to oxygen deficiency in infarcted myocardium. Revealing the underlying molecular mechanism for CPC proliferation is critical for effective MI therapy. In the present study, we set up a CoCl2-induced hypoxia model in CPCs. We found that the expression of long non-coding RNA H19 was significantly down-regulated in CPCs after hypoxia stimuli. In addition, H19 suppression attenuated the proliferation and migration of CPCs under hypoxia stress. Furthermore, we discovered that H19 regulated the proliferation and migration of CPCs through mediating the expression of Sirt1 which is a target of miR-200a-3p under hypoxia. In conclusion, our findings demonstrate a novel regulatory mechanism for the proliferation and migration of CPCs under hypoxia condition, which provides useful information for the development of new therapeutic targets for MI therapy.

Ascorbic acid induces cardiac differentiation of white adipose tissue-derived stem cells.

White adipose tissue (WAT) is the bulk of fatty tissues in humans. Enhancing the potential of WAT-derived stem cells (WATDCs) to generate cardiomyocytes may help supply sufficient number of therapeutically potent cells for heart repair in vivo. Therefore, we investigated whether ascorbic acid (AA) could facilitate the cardiac differentiation of WATDCs and the underlying mechanisms. Our results indicated that AA dose-dependently stimulates the cardiac differentiation of WATDCs, which is supported by the up-regulated expression of cardiac markers and the appearance of myotube-like cell morphologies. Time-course study showed that the front phase (0-4days) is crucial for the action of AA on cardiac differentiation, which hints that AA may take effect through enhancing the proliferation of cardiac progenitor cells. EdU assay ascertained AA indeed promotes cell growth dose-dependently in the front phase. Further investigation indicated that AA induces the phosphorylation of MEK and ERK, and the synthesis of collagen I (Col I). Interference of MEK/ERK activity or Col I synthesis blocks the cardiomyogenic activity of AA in WATDCs. These findings demonstrated that AA facilitates WATDC cardiogenesis via promoting the proliferation of cardiac progenitor cells through MEK/ERK signaling and collagen synthesis.