Development of a Mouse Cardiac Sarcoidosis Model Using Carbon Nanotubes.

Sarcoidosis, a granulomatous disorder of unknown etiology affecting multiple organs. It is often a benign disease but can have significant morbidity and mortality when the heart is involved (often presenting with clinical manifestations such as conduction irregularities and heart failure). This study addresses a critical gap in cardiac sarcoidosis (CS) research by developing a robust animal model.

Atrial Fibrosis and Inflammation in Postoperative Atrial Fibrillation: Comparative Effects of Amiodarone, Colchicine, or Exosomes.

Background: Extracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their antifibrotic/anti-inflammatory properties remain unclear.

Objectives: The purpose of this study was to conduct a head-to-head comparison of antiarrhythmic strategies to prevent postoperative AF using a rat model of sterile pericarditis.

Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation.

Extracellular vesicles (EVs) from human explant-derived cells injected directly into the atria wall muscle at the time of open chest surgery reduce atrial fibrosis, atrial inflammation, and atrial fibrillation (AF) in a rat model of sterile pericarditis. Albeit a promising solution to prevent postoperative AF, the mechanism(s) underlying this effect are unknown and it is not clear if this benefit is dependent on EV dose. To determine the dose-efficacy relationship of EVs from human explant-derived cells in a rat model of sterile pericarditis.

Prevention of atrial fibrillation after open-chest surgery with extracellular vesicle therapy.

Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent postoperative AF.

Extracellular vesicle microRNA and protein cargo profiling in three clinical-grade stem cell products reveals key functional pathways.

The cell origin-specific payloads within extracellular vesicles (EVs) mediate therapeutic bioactivity for a wide variety of stem cell types. In this study, we profiled the microRNA (miRNA) and protein cargos found within EVs produced by three clinical-grade stem cell products of different ontogenies being considered for clinical application, namely bone marrow-derived mesenchymal stromal cells (BM-MSCs), heart-derived cells (HDCs), and umbilical cord-derived MSCs (UC-MSCs). Although several miRNAs (757) and proteins (420) were found in common, each producer cell type expressed unique miRNA profiles when the most highly expressed transcripts were compared.

Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury.

Background: Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a key role in the pathology of COVID-19, several clinical trials are underway to evaluate the effect of immunomodulatory cell therapy on disease progression. However, little is known about the effect of ARDS associated pro-inflammatory mediators on transplanted stem cell function and survival, and any deleterious effects could undermine therapeutic efficacy.

Electrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection.

We have shown that calcium-activated potassium (KCa)-channels regulate fundamental progenitor-cell functions, including proliferation, but their contribution to cell-therapy effectiveness is unknown. Here, we test the participation of KCa-channels in human heart explant-derived cell (EDC) physiology and therapeutic potential. TRAM34-sensitive KCa3.

Mybl2 rejuvenates heart explant-derived cells from aged donors after myocardial infarction.

While cell therapy is emerging as a promising option for patients with ischemic cardiomyopathy (ICM), the influence of advanced donor age and a history of ischemic injury on the reparative performance of these cells are not well defined. As such, intrinsic changes that result from advanced donor age and ischemia are explored in hopes of identifying a molecular candidate capable of restoring the lost reparative potency of heart explant-derived cells (EDCs) used in cell therapy. EDCs were cultured from myocardial biopsies obtained from young or old mice 4 weeks after randomization to experimental myocardial infarction or no intervention.

Deterministic paracrine repair of injured myocardium using microfluidic-based cocooning of heart explant-derived cells.

While encapsulation of cells within protective nanoporous gel cocoons increases cell retention and pro-survival integrin signaling, the influence of cocoon size and intra-capsular cell-cell interactions on therapeutic repair are unknown. Here, we employ a microfluidic platform to dissect the impact of cocoon size and intracapsular cell number on the regenerative potential of transplanted heart explant-derived cells. Deterministic increases in cocoon size boosted the proportion of multicellular aggregates within cocoons, reduced vascular clearance of transplanted cells and enhanced stimulation of endogenous repair.

Physiologic expansion of human heart-derived cells enhances therapeutic repair of injured myocardium.

Background: Serum-free xenogen-free defined media and continuous controlled physiological cell culture conditions have been developed for stem cell therapeutics, but the effect of these conditions on the relative potency of the cell product is unknown. As such, we conducted a head-to-head comparison of cell culture conditions on human heart explant-derived cells using established in vitro measures of cell potency and in vivo functional repair.

Methods: Heart explant-derived cells cultured from human atrial or ventricular biopsies within a serum-free xenogen-free media and a continuous physiological culture environment were compared to cells cultured under traditional (high serum) cell culture conditions in a standard clean room facility.

Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Heart-Explant Derived Cell Dysfunction.

Decades of work have shown that diabetes increases the risk of heart disease and worsens clinical outcomes after myocardial infarction. Because diabetes is an absolute contraindication to heart transplant, cell therapy is increasingly being explored as a means of improving heart function for these patients with very few other options. Given that hyperglycemia promotes the generation of toxic metabolites, the influence of the key detoxification enzyme glyoxalase 1 (Glo1) on chronic hyperglycemia induced heart explant-derived cell (EDC) dysfunction was investigated.

Deterministic Encapsulation of Human Cardiac Stem Cells in Variable Composition Nanoporous Gel Cocoons To Enhance Therapeutic Repair of Injured Myocardium.

Although cocooning explant-derived cardiac stem cells (EDCs) in protective nanoporous gels (NPGs) prior to intramyocardial injection boosts long-term cell retention, the number of EDCs that finally engraft is trivial and unlikely to account for salutary effects on myocardial function and scar size. As such, we investigated the effect of varying the NPG content within capsules to alter the physical properties of cocoons without influencing cocoon dimensions. Increasing NPG concentration enhanced cell migration and viability while improving cell-mediated repair of injured myocardium.

Interleukin-6 Mediates Post-Infarct Repair by Cardiac Explant-Derived Stem Cells.

Unlabelled: Although patient-sourced cardiac explant-derived stem cells (EDCs) provide an exogenous source of new cardiomyocytes post-myocardial infarction, poor long-term engraftment indicates that the benefits seen in clinical trials are likely paracrine-mediated. Of the numerous cytokines produced by EDCs, interleukin-6 (IL-6) is the most abundant; however, its role in cardiac repair is uncertain. In this study, a custom short-hairpin oligonucleotide lentivirus was used to knockdown IL-6 in human EDCs, revealing an unexpected pro-healing role for the cytokine.