Cardiomyocyte renewal

The inaccessibility of human cardiomyocytes significantly hindered years of cardiovascular research efforts. To overcome these limitations, non-human cell sources were used as proxies to study heart function and associated diseases. Rodent models became increasingly acceptable surrogates to model the human heart either in vivo or through in vitro cultures. More recently, due to concerns regarding animal to human translation, including cross-species differences, the use of human iPSC-derived cardiomyocytes presented a renewed opportunity...

Cell cycle progression is linked to transcriptome dynamics and variations in the response of pluripotent cells to differentiation cues, mostly through unknown determinants. Here, we characterized the cell-cycle-associated transcriptome and proteome of mouse embryonic stem cells (mESCs) in naive ground state. We found that the thymine DNA glycosylase (TDG) is a cell-cycle-regulated co-factor of the tumor suppressor p53. Furthermore, TDG and p53 co-bind ESC-specific cis-regulatory elements and thereby control transcription of p53-dependent genes during self-renewal...

Precise spatiotemporal control of gene expression patterns is critical for normal development. Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), with the ability of unlimited self-renewal and differentiation into any cell type, provide a unique tool for understanding the underlying mechanism of development and disease in a dish. N6-methyl-adenosine (m6 A) modification is the most extensive internal mRNA modification, which regulates almost all aspects of mRNA metabolism and thus extensively participates in gene expression regulation...

Heart failure remains a major cause of death worldwide. There is a need to establish new management options as current treatment is frequently suboptimal. Clinical approaches based on autologous stem cell transplant is potentially a good alternative. The heart was long considered an organ unable to regenerate and renew. However, several reports imply that it may possess modest intrinsic regenerative potential. To allow for detailed characterization of cell cultures, whole transcriptome profiling was performed after 0, 7, 15, and 30 days of in vitro cell cultures (IVC) from the right atrial appendage and right atrial wall utilizing microarray technology...

BACKGROUND: Drug-induced or acquired long QT syndrome occurs as a result of the unintended disruption of cardiac repolarization due to drugs that block cardiac ion channels. These side effects have been responsible for the withdrawal of a range of drugs from market and are a common reason for termination of the development of new drugs in the preclinical stage. Existing approaches to risk prediction are expensive and overly sensitive meaning that recently there have been renewed efforts, largely driven by the comprehensive proarrhythmic assay initiative, to develop more accurate methods for allocation of proarrhythmic risk...

BACKGROUND: Induced pluripotent stem cells (iPSCs) offer potential to revolutionize regenerative medicine as a renewable source for islets, dopaminergic neurons, retinal cells, and cardiomyocytes. However, translation of these regenerative cell therapies requires cost-efficient mass manufacturing of high-quality human iPSCs. This study presents an improved three-dimensional Vertical-Wheel® bioreactor (3D suspension) cell expansion protocol with comparison to a two-dimensional (2D planar) protocol...

Static magnetic fields (SMFs) exhibit numerous biological effects and regulate the proliferation and differentiation of several adult stem cells. However, the role of SMFs in the self-renewal maintenance and developmental potential of pluripotent embryonic stem cells (ESCs) remains largely uninvestigated. Here, we show that SMFs promote the expression of the core pluripotent markers Sox2 and SSEA-1. Furthermore, SMFs facilitate the differentiation of ESCs into cardiomyocytes and skeletal muscle cells. Consistently, transcriptome analysis reveals that muscle lineage differentiation and skeletal system specification of ESCs are remarkably strengthened by SMF stimuli...

Despite unquestionable progress in interventional and pharmacologic therapies of ischemic heart disease, the number of patients with chronic ischemic heart failure is increasing and the prognosis remains poor. Repair/restoration of functional myocardium through progenitor cell-mediated (PCs) healing and renovation of injured myocardium is one of the pivotal directions in biomedical research. PCs release numerous pro-angiogenic and anti-apoptotic factors. Moreover, they have self-renewal capability and may differentiate into specialized cells that include endothelial cells and cardiomyocytes...

Cardiac-resident macrophages (CRMs) play important roles in homeostasis, cardiac function, and remodeling. Although CRMs play critical roles in cardiac regeneration of neonatal mice, their roles are yet to be fully elucidated. Therefore, this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration. During mouse cardiac ontogeny, four CRM subsets exist successively: CX3 CR1+ CCR2- Ly6C- MHCII- (MP1), CX3 CR1low CCR2low Ly6C- MHCII- (MP2), CX3 CR1- CCR2+ Ly6C+ MHCII- (MP3), and CX3 CR1+ CCR2- Ly6C- MHCII+ (MP4)...

Cardiovascular disease remains the leading cause of mortality worldwide. Cardiomyocytes are irreversibly lost due to cardiac ischemia secondary to disease. This leads to increased cardiac fibrosis, poor contractility, cardiac hypertrophy, and subsequent life-threatening heart failure. Adult mammalian hearts exhibit notoriously low regenerative potential, further compounding the calamities described above. Neonatal mammalian hearts, on the other hand, display robust regenerative capacities. Lower vertebrates such as zebrafish and salamanders retain the ability to replenish lost cardiomyocytes throughout life...

Neonatal mouse hearts have transient renewal capacity which is lost in juvenile and adult hearts. After myocardial infarction (MI) in neonatal hearts, an initial loss of cardiomyocytes occurs but it is unclear through which type of regulated cell death (RCD). In the current studies, we induced MI in neonatal and juvenile mouse hearts, and show that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrate that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine factors and direct cell-cell interaction...

AIMS: Accumulating data demonstrates that new adult cardiomyocytes (CMs) are generated throughout life from pre-existing CMs, although the absolute magnitude of CM self-renewal is very low. Modifying epigenetic histone modifications or activating the Hippo-Yap pathway have been shown to promote adult CM cycling and proliferation. Whether these interventions work through common pathways or act independently is unknown. For the first time we have determined whether lysine demethylase 4D (KDM4D)-mediated CM-specific H3K9 demethylation and Hippo pathways inhibition have additive or redundant roles in promoting CM cell cycle re-entry...

BACKGROUND: Canonical Wnt signaling is involved in a variety of biological processes including stem cell renewal and differentiation, embryonic development, and tissue regeneration. Previous studies reported the stage-specific roles of the Wnt signaling in heart development. Canonical Wnt signal activation by recombinant Wnt3a in the early phase of differentiation enhances the efficiency of myocardial cell production from pluripotent stem cells. However, the hydrophobicity of Wnt proteins results in high cost to produce the recombinant proteins and presents an obstacle to their preparation and application for therapeutics, cell therapy, or molecular analysis of Wnt signaling...

There are few stem cells in human peripheral blood (PB). Increasing the population and plasticity of stem cells in PB and applying it to regenerative medicine require suitable culture methods. In this study, leukocyte populations 250 mL of PB were collected using a blood separator before that were cultured in optimal cell culture medium for 4 to 7 days. After culturing, stemness characteristics were analyzed, and red blood cells were removed from the cultured cells. In our results, stemness markers of the leukocyte populations Sca-1+ CD45+, CD117+ CD45+, and very small embryonic-like stem cells CD34+ Lin- CD45- and CXCR4+ Lin- CD45- were significantly increased...

Hypoimmunogenic human pluripotent stem cells (hPSCs) are expected to serve as an unlimited cell source for generating universally compatible "off-the-shelf" cell grafts. However, whether the engineered hypoimmunogenic hPSCs still preserve their advantages of unlimited self-renewal and multilineage differentiation to yield functional tissue cells remains unclear. Here, we systematically studied the self-renewal and differentiation potency of three types of hypoimmunogenic hPSCs, established through the biallelic lesion of B2M gene to remove all surface expression of classical and nonclassical HLA class I molecules (B2Mnull ), biallelic homologous recombination of nonclassical HLA-G1 to the B2M loci to knockout B2M while expressing membrane-bound β2m-HLA-G1 fusion proteins (B2MmHLAG ), and ectopic expression of soluble and secreted β2m-HLA-G5 fusion proteins in B2MmHLAG hPSCs (B2Mm/sHLAG ) in the most widely used WA09 human embryonic stem cells...

Ischemic heart disease is a leading cause of death worldwide. Myocardial infarction (MI) results in cardiac damage due to cell death and insufficient cardiomyocyte self-renewal. Ferroptosis, a novel type of cell death, has recently been shown as a key cause of cardiomyocyte death after MI. However, the complicated regulation mechanisms involved in ferroptosis, especially how ferroptosis is integrated into classical cell survival/death pathways, are still unclear. Here, we discovered that HIP-55, a novel adaptor protein, acts as a hub protein for the integration of the ferroptosis mechanism into the classical AKT cell survival and MAP4K1 cell death pathways for MI injury...

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+ RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi )...

Pluripotent embryonic stem cells (ESCs) can self-renew indefinitely and are able to differentiate into all three embryonic germ layers. Synaptosomal-associated protein 29 (Snap29) is implicated in numerous intracellular membrane trafficking pathways, including autophagy, which is involved in the maintenance of ESC pluripotency. However, the function of Snap29 in the self-renewal and differentiation of ESCs remains elusive. Here, we show that Snap29 depletion via CRISPR/Cas does not impair the self-renewal and expression of pluripotency-associated factors in mouse ESCs...

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival...

Heart disease is the primary cause of death worldwide. Even though extensive research has been done, and many pharmacological and surgical treatments have been introduced to treat heart disease, the mortality rate still remains high. Gene therapy is widely used to understand molecular mechanisms of myocardial infarction and to treat cardiomyocyte loss. It was reported that adult cardiomyocytes proliferate at a very low rate; thus, targeting their proliferation has become a new regenerative therapeutic approach...