Human induced pluripotent stem cell-derived (hiPSC) cardiomyocytes are a promising source for regenerative therapy. To realize this therapy, however, their engraftment potential after their injection into the host heart should be improved. Here, we established an efficient method to analyze the cell cycle activity of hiPSC cardiomyocytes using a fluorescence ubiquitination-based cell cycle indicator (FUCCI) system. In vitro high-throughput screening using FUCCI identified a retinoic acid receptor (RAR) agonist, Am80, as an effective cell cycle activator in hiPSC cardiomyocytes. The transplantation of hiPSC cardiomyocytes treated with Am80 before the injection significantly enhanced the engraftment in damaged mouse heart for 6 months. Finally, we revealed that the activation of endogenous Wnt pathways through both RARA and RARB underlies the Am80-mediated cell cycle activation. Collectively, this study highlights an efficient method to activate cell cycle in hiPSC cardiomyocytes by Am80 as a means to increase the graft size after cell transplantation into a damaged heart.
Induced Pluripotent Stem Cells , Myocytes, Cardiac , Animals , Mice , Humans , Receptors, Retinoic Acid/metabolism , Induced Pluripotent Stem Cells/metabolism , Cell Cycle , Cell Differentiation
BACKGROUND: Spontaneous isolated dissection of abdominal visceral arteries without aortic dissection is rare and its pathology and prognosis are not yet clear; therefore, therapeutic strategies for this disease have not been established. The present multi-institution investigational study analyzed the clinical features of patients with spontaneous isolated dissection of abdominal visceral arteries. METHODS: A total of 36 patients diagnosed as spontaneous isolated dissection of abdominal visceral arteries from January 2010 to October 2016 were enrolled. The medical data of the patients were retrospectively reviewed. Imaging characteristics were evaluated. Spontaneous isolated dissection of abdominal visceral arteries was detected on upper abdominal computed tomography examination in almost patients, and was detected on magnetic resonance imaging in one patient. RESULTS: Of the 36 cases, 26 cases involved the superior mesenteric artery dissection, nine involved the celiac artery, two involved the splenic artery, one involved the common hepatic artery, one involved the gastroduodenal artery and one involved the left gastric artery. Among the 36 patients, 20 had hypertension and 14 were current smokers. Additionally, only one patient had diabetes and four patients had dyslipidemia. Moreover, 32 cases complained of pain including abdominal pain and back pain, one had cough and three had no symptoms. Of the 36 patients, 34 cases (94.4%) were treated conservatively, and two (5.6%) required intravascular treatment. All patients were discharged without complications. CONCLUSIONS: Our findings indicate that hypertension and smoking might be closely involved in the pathogenesis of spontaneous isolated dissection of abdominal visceral arteries, whereas dyslipidemia and diabetes might be less involved. Additionally, few asymptomatic patients were accidentally diagnosed, indicating that the absence of symptoms cannot be used to rule out the presence of this disease. Randomized clinical trials cannot be performed because a considerable number of cases are required. Therefore, detailed descriptions of clinical features, as provided in our report, are important.
Objective: Little is known about the long-term effects of renin-angiotensin system inhibitors (RASI) on cardiovascular events in patients after acute myocardial infarction (AMI) with ischaemic mitral regurgitation (IMR). The purpose of this study was to investigate the association of RASI with the incidence of adverse cardiac events in patients with or without IMR after AMI. Methods: We reviewed charts of 1208 consecutive patients admitted with AMI who underwent emergency coronary angiography between 2000 and 2012. After excluding patients who died within 30 days, 551 patients were diagnosed to have mild or greater MR by transthoracic echocardiography (patients with IMR); the remaining 505 patients had no or trivial MR (non-IMR patients). Results: Of the study patients, 395 (72%) patients with IMR and 403 (80%) non-IMR patients received RASI. Survival analysis showed that freedom from cardiac death and the composite of cardiac death and heart failure (HF) was significantly higher in patients with IMR receiving RASI than in those not receiving RASI (P<0.001 and P<0.001, respectively). Moreover, adjusted survival analysis using the inverse probability treatment weighting method showed a significant association of RASI therapy with reduced cardiac death (P=0.010) and the composite of cardiac death and HF (P=0.044) in patients with IMR. However, in non-IMR patients, there were no significant associations between RASI therapy and the outcome measures. Conclusions: RASI therapy was associated with a lower incidence of adverse cardiac events in patients with IMR after AMI, but not in patients without IMR.
