Cardiac muscle patches containing four types of cardiac cells derived from human pluripotent stem cells improve recovery from cardiac injury in mice.

Aims: We have shown that human cardiac muscle patches (hCMPs) containing three different types of cardiac cells-cardiomyocytes (CMs), smooth muscle cells (SMCs), and endothelial cells (ECs), all of which were differentiated from human pluripotent stem cells (hPSCs)-significantly improved cardiac function, infarct size, and hypertrophy in a pig model of myocardial infarction (MI). However, hPSC-derived CMs (hPSC-CMs) are phenotypically immature, which may lead to arrhythmogenic concerns; thus, since hPSC-derived cardiac fibroblasts (hPSC-CFs) appear to enhance the maturity of hPSC-CMs, we compared hCMPs containing hPSC-CMs, -SMCs, -ECs, and -CFs (4TCC-hCMPs) with a second hCMP construct that lacked hPSC-CFs but was otherwise identical [hCMP containing hPSC-CMs, -AECs, and -SMCs (3TCC-hCMPs)].

Methods And Results: hCMPs were generated in a fibrin scaffold.

Transgenic RFP-RPS-30 strain of the nematode Caenorhabditis elegans as a biomonitor for environmental pollutants.

Environmental pollutants are recognized as one of the major concerns for public health. The free-living nematode Caenorhabditis elegans are widely used to evaluate the toxicity of environmental contaminants in biomonitoring researches. In the present study, a new transgenic strain, rps-30 ;RFP-RPS-30 was generated, with constitutively active rps-30 promoter used to control the expression of RFP-RPS-30 fusion protein.

Reduced rotational flows enable the translation of surface-rolling microrobots in confined spaces.

Biological microorganisms overcome the Brownian motion at low Reynolds numbers by utilizing symmetry-breaking mechanisms. Inspired by them, various microrobot locomotion methods have been developed at the microscale by breaking the hydrodynamic symmetry. Although the boundary effects have been extensively studied for microswimmers and employed for surface-rolling microrobots, the behavior of microrobots in the proximity of multiple wall-based "confinement" is yet to be elucidated.

Metabolic labeling of cardiomyocyte-derived small extracellular-vesicle (sEV) miRNAs identifies miR-208a in cardiac regulation of lung gene expression.

Toxoplasma gondii uracil phosphoribosyltransferase (UPRT) converts 4-thiouracil (4TUc) into 4-thiouridine (4TUd), which is incorporated into nascent RNAs and can be biotinylated, then labelled with streptavidin conjugates or isolated via streptavidin-affinity methods. Here, we generated mice that expressed T. gondii UPRT only in cardiomyocytes ( UPRT mice) and tested our hypothesis that CM-derived miRNAs ( miRs) are transferred into remote organs after myocardial infarction (MI) by small extracellular vesicles (sEV) that are released from the heart into the peripheral blood ( sEV).

Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity.

Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear.

Zyxin and actin structure confer anisotropic YAP mechanotransduction.

Tissues and the embedded cells experience anisotropic deformations due to their functions and anatomical locations. The resident cells, such as tenocytes and muscle cells, are often restricted by their extracellular matrix and organize parallel to their major loading direction, yet most studies on cellular responses to strains use isotropic substrates without predetermined organizations. To understand how confined cells sense and respond to anisotropic loading, we combine cell patterning and uniaxial stretch to have precise geometric control.

A three-dimensional culture system for generating cardiac spheroids composed of cardiomyocytes, endothelial cells, smooth-muscle cells, and cardiac fibroblasts derived from human induced-pluripotent stem cells.

Cardiomyocytes (CMs), endothelial cells (ECs), smooth-muscle cells (SMCs), and cardiac fibroblasts (CFs) differentiated from human induced-pluripotent stem cells (hiPSCs) are the fundamental components of cell-based regenerative myocardial therapy and can be used as models for mechanistic studies and drug testing. However, newly differentiated hiPSC-CMs tend to more closely resemble fetal CMs than the mature CMs of adult hearts, and current techniques for improving CM maturation can be both complex and labor-intensive. Thus, the production of CMs for commercial and industrial applications will require more elementary methods for promoting CM maturity.

Sex differences in heart mitochondria regulate diastolic dysfunction.

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts.

Turning back the clock: A concise viewpoint of cardiomyocyte cell cycle activation for myocardial regeneration and repair.

Patients with acute myocardial infarction (MI) could progress to end-stage congestive heart failure, which is one of the most significant problems in public health. From the molecular and cellular perspective, heart failure often results from the loss of cardiomyocytes-the fundamental contractile unit of the heart-and the damage caused by myocardial injury in adult mammals cannot be repaired, in part because mammalian cardiomyocytes undergo cell-cycle arrest during the early perinatal period. However, recent studies in the hearts of neonatal small and large mammals suggest that the onset of cardiomyocyte cell-cycle arrest can be reversed, which may lead to the development of entirely new strategies for the treatment of heart failure.

UCHL1 protects against ischemic heart injury via activating HIF-1α signal pathway.

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) has been thought to be a neuron specific protein and shown to play critical roles in Parkinson's Disease and stroke via de-ubiquiting and stabilizing key pathological proteins, such as α-synuclein. In the present study, we found that UCHL1 was significantly increased in both mouse and human cardiomyocytes following myocardial infarction (MI). When LDN-57444, a pharmacological inhibitor of UCHL1, was used to treat mice subjected to MI surgery, we found that administration of LDN-57444 compromised cardiac function when compared with vehicle treated hearts, suggesting a potential protective role of UCHL1 in response to MI.

Engineering of thick human functional myocardium via static stretching and electrical stimulation.

Human cardiac-muscle patches (hCMPs) constructed from induced pluripotent stem cells derived cardiomyocytes (iCMs) can replicate the genetics of individual patients, and consequently be used for drug testing, disease modeling, and therapeutic applications. However, conventional hCMPs are relatively thin and contain iCMs with fetal cardiomyocyte structure and function. Here, we used our layer-by-layer (lbl) fabrication to construct thicker (>2.

The anti-aging protein Klotho affects early postnatal myogenesis by downregulating Jmjd3 and the canonical Wnt pathway.

Modulating the number of muscle stems cells, called satellite cells, during early postnatal development produces long-term effects on muscle growth. We tested the hypothesis that high expression levels of the anti-aging protein Klotho in early postnatal myogenesis increase satellite cell numbers by influencing the epigenetic regulation of genes that regulate myogenesis. Our findings show that elevated klotho expression caused a transient increase in satellite cell numbers and slowed muscle fiber growth, followed by a period of accelerated muscle growth that leads to larger fibers.

The challenges and optimization of cell-based therapy for cardiovascular disease.

With the hope of achieving real cardiovascular repair, cell-based therapy raised as a promising strategy for the treatment of cardiovascular disease (CVD) in the past two decades. Various types of cells have been studied for their reparative potential for CVD in the ensuing years. Despite the exciting results from animal experiments, the outcome of clinical trials is unsatisfactory and the development of cell-based therapy for CVD has hit a plateau nowadays.

Upregulated galectin-1 in Angiostrongylus cantonensis L5 reduces body fat and increases oxidative stress tolerance.

Background: Angiostrongylus cantonensis L5, parasitizing human cerebrospinal fluid, causes eosinophilic meningitis, which is attributed to tissue inflammatory responses caused primarily by the high percentage of eosinophils. Eosinophils are also involved in killing helminths, using the peroxidative oxidation and hydrogen peroxide (HO) generated by dismutation of superoxide produced during respiratory burst. In contrast, helminthic worms have evolved to attenuate eosinophil-mediated tissue inflammatory responses for their survival.

MicroRNA-181c-5p modulates phagocytosis efficiency in bone marrow-derived macrophages.

Objective And Design: Phagocytosis and clearance of apoptotic cells are essential for inflammation resolution, efficient wound healing, and tissue homeostasis. MicroRNAs are critical modulators of macrophage polarization and function. The current study aimed to investigate the role of miR-181c-5p in macrophage phagocytosis.

Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms.

The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.

Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model.

Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout in mice is embryonically lethal.

Extracellular vesicles in cardiovascular disease: Biological functions and therapeutic implications.

Extracellular vesicles (EVs), including exosomes and microvesicles, are lipid bilayer particles naturally released from the cell. While exosomes are formed as intraluminal vesicles (ILVs) of the multivesicular endosomes (MVEs) and released to extracellular space upon MVE-plasma membrane fusion, microvesicles are generated through direct outward budding of the plasma membrane. Exosomes and microvesicles have same membrane orientation, different yet overlapping sizes; their cargo contents are selectively packed and dependent on the source cell type and functional state.

Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response.

Heat shock protein 22 (Hsp22) is a small heat shock protein predominantly expressed in skeletal and cardiac muscle. Previous studies indicate that Hsp22 plays a vital role in protecting the heart against cardiac stress. However, the essential role of Hsp22 in the heart under physiological conditions remains largely unknown.

TT-10-loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction.

The meager regenerative capacity of adult mammalian hearts appears to be driven by the proliferation of endogenous cardiomyocytes; thus, strategies targeting mechanisms of cardiomyocyte cell cycle regulation, such as the Hippo/Yes-associated protein (Hippo/Yap) pathway, could lead to the development of promising therapies for heart disease. The pharmacological product TT-10 increases cardiomyocyte proliferation by upregulating nuclear Yap levels. When intraperitoneal injections of TT-10 were administered to infarcted mouse hearts, the treatment promoted cardiomyocyte proliferation and was associated with declines in infarct size 1 week after administration, but cardiac function worsened at later time points.

Transcription factor MEF2D is required for the maintenance of MLL-rearranged acute myeloid leukemia.

Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises ∼10% of all AML cases and portends poor outcomes. Much remains uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a super-enhancer-associated, highly expressed gene in MLL-r AML.

Increased m6A-RNA methylation and FTO suppression is associated with myocardial inflammation and dysfunction during endotoxemia in mice.

Endotoxemia triggers life-threatening immune and cardiovascular response that leads to tissue damage, multi-organ failure, and death. The understanding of underlying molecular mechanisms is still evolving. N6-methyladenosine (m6A)-RNA modification plays key regulatory role in numerous biological processes.

A 3D Bioprinted In Vitro Model of Pulmonary Artery Atresia to Evaluate Endothelial Cell Response to Microenvironment.

Vascular atresia are often treated via transcatheter recanalization or surgical vascular anastomosis due to congenital malformations or coronary occlusions. The cellular response to vascular anastomosis or recanalization is, however, largely unknown and current techniques rely on restoration rather than optimization of flow into the atretic arteries. An improved understanding of cellular response post anastomosis may result in reduced restenosis.