Search

Background: Multilineage-differentiating stress-enduring (Muse) cells, which have a high potential for pluripotency, reside in the bone marrow (BM). Purpose: To clarify the efficiency of S1PR2 agonist to mobilizes endogenous Muse cells into peripheral blood from the BM for tissue repair after AMI. Methods: Japanese white rabbits underwent 30 min of coronary occlusion and 2 weeks of reperfusion. S1PR2 agonist SID46371153 (10 mg/kg, s.c.) or vehicle was administered at 30 min after reperfusion. The number of SSEA3+ and CD44+ double positive Muse cells in the peripheral blood was measured by FACS at 12 h after AMI. Results: The number of Muse cells in the blood significantly increased in the S1PR2 agonist group than in the control and sham groups. The number of Muse cells was the highest in the S1PR2 agonist group (320±62/100 μL) and higher in the vehicle group (208±53/100 μL) than in the sham group (78±20/100 μL). The number of Muse cells in the S1PR2 agonist group was decreased by S1PR2 antagonist to the level of vehicle group. The infarct size as a percentage of the left ventricle (LV) was significantly smaller in the S1PR2 agonist group (19.9±1.9%) than in the vehicle group (24.6±3.8%).The reduction in the infarct size in the S1PR2 agonist was blocked by S1PR2 antagonist (22.8±2.3%). S1PR2 antagonist by itself enlarged the MI size (26.6±1.4%). Functional recovery (EF, FS, ±dP/dt) in each group was correlated with the number of Muse cells. The increase in Muse cells number by S1PR2 agonist was completely abolished by S1PR2-specific antagonist JTE-013 (5 mg/kg, s.c.). Migration of Muse cells towards AMI serum and SID46371153 was pharmacologically (JTE-013) proven to be mediated through S1P-S1PR2 axis. Culture of peripheral blood mononuclear cells demonstrated the presence of Muse cells expressing Nanog, GATA4 and Nkx2.5, which differentiated into cardiomyocyte-like cells with positive troponin T and α-actinin, and endothelial-like cells with positive CD31. S1PR2 agonist significantly reduced the myocardial infarct size and improved LV function and remodeling as compared to the controls, which were completely abolished by JTE-013. S1PR2 agonist accelerated the homing of GFP+-Muse cells from the BM to the infarcted heart and expressed cardiac troponin-I, α-actinin, connexin 43 and CD31, suggesting the potential ability of endogenous Muse cells to differentiate into cardiomyocytes and microvessels. Conclusions: S1PR2 agonist is a mobilizer of endogenous Muse cells from the BM and might be a novel strategy for the regenerative therapy of AMI. [ABSTRACT FROM AUTHOR]

Introduction: Using speckle tracking echocardiography (STE), emerging attention is brought to left atrium (LA) that is very complex due to close coupling with left ventricle (LV). LA volume (LAV) and emptying function (LAEF) reflect diastolic function and may serve as a predictor for cardiovascular outcomes. We sought to examine the relation between LV and LA properties in hypertension (HTN) by 3-dimensional STE (3D-STE). Methods: We measured LAV, LAEF and LA strain and estimated LA stiffness in 58 controls (age 67±11), 60 HTN without hypertrophy (LVH-) (69±11), 76 LVH+ (70±11) and 102 hypertensive heart failure (HHF) {40 HF with preserved EF (HFpEF, 77±14) and 62 HF with reduced EF (HFrEF, 68±16)}. We measured LV mass, EF, strain and E/e'. Pulmonary capillary wedge pressure (PCWP) was calculated as 10.8 - 12.4 x log (active LAEF / minimum LAV) as we reported. We estimated Tau and LV end-diastolic stress as isovolumic relaxation time / (ln 0.9 x systolic BP - ln PCWP) and as PCWP x end-diastolic dimension / thickness. LV myocardial and LA chamber stiffness was estimated as LV stress / strain and as PCWP / LAV change. Results: There was no difference in BP among HTN. LVEF in HFrEF decreased associated with increased LV mass and systolic stress (LVEF: control; 67±6, LVH-; 69±6, LVH+; 67±9, HFpEF; 62±9, HFrEF; 38±8*%, *p<0.05 vs control). Tau was prolonged even in LVH- (35±13, 43±15*, 52±17*, 59±16*, 67±19*ms). Stiffness increased in HHF groups (LV stiffness: 0.6±0.3, 0.6±0.4, 0.6±0.3, 0.9±0.8*, 2.3±1.7*, LA stiffness: 0.3±0.1, 0.3±0.2, 0.4±0.2, 0.7±0.5*, 0.9±0.6*mmHg/ml) associated with increased PCWP and LV diastolic stress (PCWP: 7±3, 8±4, 9±4, 15±4*, 17±5*mmHg, diastolic stress: 11±4, 10±8, 11±7, 16±6*, 24±11*Kdynes/cm2). Total LAEF and LA strain gradually decreased from LVH- to HFrEF, whereas active LAEF decreased in HHF groups (36±10, 37±11, 34±10, 20±10*, 17±10*%) associated with increased PCWP and stiffness. On multivariate analysis, LV stiffness is an independent predictor for HHF among STE parameters. Conclusions: LA properties were significantly affected by LV diastolic remodeling by pressure overload. HFrEF has the most negative impact on LA properties. Noninvasive assessment of the relation between LA and LV properties by STE may have a clinical potential. [ABSTRACT FROM AUTHOR]

Background: Multilineage-differentiating stress-enduring (Muse) cells, which show high-level pluripotency, reside in the bone marrow (BM) as ~0.03% of the mononucleated fraction. We investigated whether intravenously administered human xenograft Muse cells could be mobilized to the ischemic myocardium, reduce the myocardial infarct size, and improve the cardiac function in a miniature pig model of AMI like the rabbit model. Methods: Using human BM-MSCs, Muse cells were collected as SSEA-3+ (xenograft Muse) cells by flow cytometry. In a 30-minute coronary occlusion and reperfusion model using miniature pigs (10kg), saline (vehicle group) and 1x107 of human xenograft Muse cells labeled with GFP (Muse group) were intravenously infused at 24 hours after MI. The MI size, cardiac function, and blood tests were evaluated at 2 weeks post-MI. We examined whether arrhythmia appeared using an ILR (implantable loop recorder) for 2 weeks. The general pathology of the heart was evaluated at 2 weeks post-MI. Confocal microscopy was performed to evaluate the regeneration of the myocardium. Results: The MI size measured using Masson trichrome staining was significantly smaller in the Muse group (10.5±3.3%) than in the vehicle group (20.5±2.3%) (P<0.05). At 2 weeks post-MI, a smaller left ventricular (LV) dimension and increased LV ejection fraction were seen in the Muse group as compared with the vehicle group with a statistically significant difference (P<0.05, P<0.001, respectively). Using the ILR, we confirmed that arrhythmias were not recorded in either group. The number of CD31-positive microvessels was significantly greater in regions surrounding the infarct area in the Muse group than in the vehicle group, suggesting that integrated Muse cells may have contributed to neovascularization. Integrated GFP(+)-Muse cells were positive for troponin I, suggesting the spontaneous differentiation of cardiomyocytes from Muse cells. Conclusions: The post-infarct intravenous administration of human xenograft Muse cells reduced the myocardial infarct size and improved cardiac remodeling and functioning through the regeneration of cardiomyocytes and microvessels in miniature pigs. Muse cell transplantation may be a promising strategy for AMI treatment. [ABSTRACT FROM AUTHOR]