This study shows that spiral waves in atrial cardiomyocyte monolayers can be terminated effectively by a light-induced depolarizing current, produced by the arrhythmogenic substrate itself, upon optogenetic engineering. These results provide proof-of-concept for shockless defibrillation.

Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin 2 /Sca-1 + /cKit + hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin 2 /Sca-1 + /cKit + cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin 2 /Sca-1 + /cKit + cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.

Mesenchymal stem cells (MSCs) are considered as promising candidates for new clinical trials of cell therapies. Bone marrow (BM) was the first source reported to contain MSCs; however, using it may be detrimental due to the highly invasive aspiration procedures. More recently, adipose tissue, attainable by a less invasive method, has been introduced as an alternative source of MSCs. So far, MSCs derived from these two sources have been compared in different characters; however, one of the main properties, i.e., the expression of chemokine receptors, has been ignored in these comparisons. In the present study, human MSCs were derived from bone marrow and adipose tissues and characterized by their expression of some cell surface antigens and also differentiation capacity. The expression of five selected chemokine receptors, which seems to be important in cell homing, was also compared. Semiquantitative reverse transcription-polymerase chain reaction method was used to assess gene expression levels of these chemokine receptors. Our results indicate that expression of these receptors in human MSCs, derived from adipose tissue, was higher than MSCs from bone marrow. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissues. Therefore, MSCs from adipose tissue may show a better migration and homing capacity and they might be a better candidate for therapeutic purposes.

Background— Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current ( I K,ACh-c ) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how I K,ACh-c contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of I K,ACh-c blockade and Kir3.x downregulation on atrial fibrillation. Methods and Results— Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3 - or Kcnj5 -specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P <0.0001) in atrial cultures during reentry, indicating the presence of I K,ACh-c . Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P <0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P <0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of I K,ACh-c prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (eg, >50% reduction in atrial fibrillation inducibility after I K,ACh-c blockade). Conclusions— Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I K,ACh-c . This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.