Surface engineering enhances the therapeutic potential of systemically delivered extracellular vesicles following acute myocardial infarction.

The objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere-derived cell (CDC) extracellular vesicles (EVs) delivered via intramyocardial and intravenous routes following acute myocardial infarction (MI). Cardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following MI. While EVs secreted by CDCs have shown efficacy in promoting cardiac repair in preclinical models of MI, their translational potential is limited by their biodistribution and requirement for intramyocardial delivery.

Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice.

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain.

Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis development is unclear. To recapitulate the involvement of macrophages in the development of pulmonary fibrosis, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts.

Modeling Mechanical Activation of Macrophages During Pulmonary Fibrogenesis for Targeted Anti-Fibrosis Therapy.

Pulmonary fibrosis, as seen in idiopathic pulmonary fibrosis (IPF) and COVID-induced pulmonary fibrosis, is an often-fatal lung disease. Increased numbers of immune cells such as macrophages were shown to accumulate in the fibrotic lung, but it is unclear how they contribute to the development of fibrosis. To recapitulate the macrophage mechanical activation in the fibrotic lung tissue microenvironment, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts.

Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases.

Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large-scale manufacturing of therapeutic-grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases.

Modified GAN Augmentation Algorithms for the MRI-Classification of Myocardial Scar Tissue in Ischemic Cardiomyopathy.

Contrast-enhanced cardiac magnetic resonance imaging (MRI) is routinely used to determine myocardial scar burden and make therapeutic decisions for coronary revascularization. Currently, there are no optimized deep-learning algorithms for the automated classification of scarred vs. normal myocardium.

Neutrophils aid cellular therapeutics by enhancing glycoengineered stem cell recruitment and retention at sites of inflammation.

The efficacy of cell-based therapies relies on targeted payload delivery and enhanced cell retention. In vitro and in vivo studies suggest that the glycoengineering of mesenchymal and cardiosphere-derived cells (CDCs) may enhance such recruitment at sites of injury. We evaluated the role of blood cells in amplifying this recruitment.

CBR3 V244M is associated with LVEF reduction in breast cancer patients treated with doxorubicin.

Background: The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts.

Objectives: This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment.

Fast Stereolithography Printing of Large-Scale Biocompatible Hydrogel Models.

Large size cell-laden hydrogel models hold great promise for tissue repair and organ transplantation, but their fabrication using 3D bioprinting is limited by the slow printing speed that can affect the part quality and the biological activity of the encapsulated cells. Here a fast hydrogel stereolithography printing (FLOAT) method is presented that allows the creation of a centimeter-sized, multiscale solid hydrogel model within minutes. Through precisely controlling the photopolymerization condition, low suction force-driven, high-velocity flow of the hydrogel prepolymer is established that supports the continuous replenishment of the prepolymer solution below the curing part and the nonstop part growth.

Monocyte recruitment and fate specification after myocardial infarction.

Monocytes are critical mediators of the inflammatory response following myocardial infarction (MI) and ischemia-reperfusion injury. They are involved in both initiation and resolution of inflammation and play an integral role in cardiac repair. The antagonistic nature of their function is dependent on their subset heterogeneity and biphasic response following injury.

CDC-derived extracellular vesicles reprogram inflammatory macrophages to an arginase 1-dependent proangiogenic phenotype.

Macrophages play a pivotal role in tissue repair following myocardial infarction (MI). In response to injury, they exist along a spectrum of activation states tightly regulated by their microenvironment. Cardiosphere-derived cells (CDCs) have been shown to mediate cardioprotection via modulation of the macrophage response.

Exosomes Engineered to Express a Cardiomyocyte Binding Peptide Demonstrate Improved Cardiac Retention in Vivo.

Injury to the heart results in cardiomyocyte cell death and can lead to pathological remodeling of remaining cells, contributing to heart failure. Despite the therapeutic potential of new drugs and small molecules, there remains a gap in the ability to efficiently deliver cardioprotective agents in a cell specific manner while minimizing nonspecific delivery to other organs. Exosomes derived from cardiosphere-derived cells (CDCs) have been shown to stimulate angiogenesis, induce endogenous cardiomyocyte proliferation and modulate cardiomyocyte apoptosis and hypertrophy.

Therapeutic Potential of Engineered Extracellular Vesicles.

Extracellular vesicles (EVs) comprise a heterogeneous group of small membrane vesicles, including exosomes, which play a critical role in intracellular communication and regulation of numerous physiological processes in health and disease. Naturally released from virtually all cells, these vesicles contain an array of nucleic acids, lipids and proteins which they transfer to target cells within their local milieu and systemically. They have been proposed as a means of "cell-free, cell therapy" for cancer, immune disorders, and more recently cardiovascular disease.

Inhibiting Extracellular Vesicle Release from Human Cardiosphere Derived Cells with Lentiviral Knockdown of nSMase2 Differentially Effects Proliferation and Apoptosis in Cardiomyocytes, Fibroblasts and Endothelial Cells In Vitro.

Numerous studies have shown a beneficial effect of cardiosphere-derived cell (CDC) therapy on regeneration of injured myocardium. Paracrine signaling by CDC secreted exosomes may contribute to improved cardiac function. However, it has not yet been demonstrated by a genetic approach that exosome release contributes to the therapeutic effect of transplanted CDCs.

Cholesterol and hematopoietic stem cells: inflammatory mediators of atherosclerosis.

Atherosclerosis causing heart attack and stroke is the leading cause of death in the modern world. Therapy for end-stage atherosclerotic disease using CD34(+) hematopoietic cells has shown promise in human clinical trials, and the in vivo function of hematopoietic and progenitor cells in atherogenesis is becoming apparent. Inflammation plays a central role in the pathogenesis of atherosclerosis.

LDL cholesterol modulates human CD34+ HSPCs through effects on proliferation and the IL-17 G-CSF axis.

Background: Hypercholesterolemia plays a critical role in atherosclerosis. CD34+ CD45dim Lineage- hematopoietic stem/progenitor cells (HSPCs) give rise to the inflammatory cells linked to atherosclerosis. In mice, high cholesterol levels mobilize HSPCs into the bloodstream, and promote their differentiation to granulocytes and monocytes.

Sox10-MCS5 enhancer dynamically tracks human oligodendrocyte progenitor fate.

In this study, we sought to establish a novel method to prospectively and dynamically identify live human oligodendrocyte precursor cells (OPCs) and oligodendrocyte lineage cells from brain dissociates and pluripotent stem cell culture. We selected a highly conserved enhancer element of the Sox10 gene, known as MCS5, which directs reporter expression to oligodendrocyte lineage cells in mouse and zebrafish. We demonstrate that lentiviral Sox10-MCS5 induced expression of GFP at high levels in a subpopulation of human CD140a/PDGFαR-sorted OPCs as well as their immature oligodendrocyte progeny.

Statins enhance clonal growth of late outgrowth endothelial progenitors and increase myocardial capillary density in the chronically ischemic heart.

Background: Coronary artery disease and ischemic heart disease are leading causes of heart failure and death. Reduced blood flow to heart tissue leads to decreased heart function and symptoms of heart failure. Therapies to improve heart function in chronic coronary artery disease are important to identify.

Statin treatment of adult human glial progenitors induces PPAR gamma-mediated oligodendrocytic differentiation.

The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells.

Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation.

Objective: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate.

Methods: We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived.