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Objectives Vitronectin (VTN) has been widely used for the maintenance and expansion of human pluripotent stem cells (hPSCs) as feeder‐free conditions. However, the effect of VTN on hPSC differentiation remains unclear. Here, we investigated the role of VTN in early haematopoietic development of hPSCs. Materials and Methods A chemically defined monolayer system was applied to study the role of different matrix or basement membrane proteins in haematopoietic development of hPSCs. The role of integrin signalling in VTN‐mediated haematopoietic differentiation was investigated by integrin antagonists. Finally, small interfering RNA was used to knock down integrin gene expression in differentiated cells. Results We found that the haematopoietic differentiation of hPSCs on VTN was far more efficient than that on Matrigel that is also often used for hPSC culture. VTN promoted the fate determination of endothelial‐haematopoietic lineage during mesoderm development to generate haemogenic endothelium (HE). Moreover, we demonstrated that the signals through αvβ3 and αvβ5 integrins were required for VTN‐promoted haematopoietic differentiation. Blocking αvβ3 and αvβ5 integrins by the integrin antagonists impaired the development of HE, but not endothelial‐to‐haematopoietic transition (EHT). Finally, both αvβ3 and αvβ5 were confirmed acting synergistically for early haematopoietic differentiation by knockdown the expression of αv, β3 or β5. Conclusion The established VTN‐based monolayer system of haematopoietic differentiation of hPSCs presents a valuable platform for further investigating niche signals involved in human haematopoietic development.

Hematopoietic differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic cell and gene regulatory networks but often generates blood cells that lack natural function. Here, we performed extensive single-cell transcriptomic analyses to map fate choices and gene expression patterns during hematopoietic differentiation of hPSCs and showed that oxidative metabolism was dysregulated during in vitro directed differentiation. Applying hypoxic conditions at the stage of endothelial-to-hematopoietic transition in vitro effectively promoted the development of arterial specification programs that governed the generation of hematopoietic progenitor cells (HPCs) with functional T cell potential. Following engineered expression of the anti-CD19 chimeric antigen receptor, the T cells generated from arterial endothelium-primed HPCs inhibited tumor growth both in vitro and in vivo. Collectively, our study provides benchmark datasets as a resource to further understand the origins of human hematopoiesis and represents an advance in guiding in vitro generation of functional T cells for clinical applications.

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Background Heart failure (HF) with mid-range ejection fraction (EF) (HFmrEF) has attracted increasing attention in recent years. However, the understanding of HFmrEF remains limited, especially among Asian patients. Therefore, analysis of a Chinese HF registry was undertaken to explore the clinical characteristics and prognosis of HFmrEF. Methods A total of 755 HF patients from a multi-centre registry were classified into three groups based on EF measured by echocardiogram at recruitment: HF with reduced EF (HFrEF) ( n = 211), HFmrEF ( n = 201), and HF with preserved EF (HFpEF) ( n = 343). Clinical data were carefully collected and analyzed at baseline. The primary endpoint was all-cause mortality and cardiovascular mortality while the secondary endpoints included hospitalization due to HF and major adverse cardiac events (MACE) during 1-year follow-up. Cox regression and Logistic regression were performed to identify the association between the three EF strata and 1-year outcomes. Results The prevalence of HFmrEF was 26.6% in the observed HF patients. Most of the clinical characteristics of HFmrEF were intermediate between HFrEF and HFpEF. But a significantly higher ratio of prior myocardial infarction ( p = 0.002), ischemic heart disease etiology ( p = 0.004), antiplatelet drug use ( p = 0.009), angioplasty or stent implantation ( p = 0.003) were observed in patients with HFmrEF patients than those with HFpEF and HFrEF. Multivariate analysis showed that the HFmrEF group presented a better prognosis than HFrEF in all-cause mortality [ p = 0.022, HR (95%CI): 0.473(0.215–0.887)], cardiovascular mortality [ p = 0.005, HR (95%CI): 0.270(0.108–0.672)] and MACE [ p = 0.034, OR (95%CI): 0.450(0.215–0.941)] at 1 year. However, no significant differences in 1-year outcomes were observed between HFmrEF and HFpEF. Conclusion HFmrEF is a distinctive subgroup of HF. The strikingly prevalence of ischemic history among patients with HFmrEF might indicate a key to profound understanding of HFmrEF. Patients in HFmrEF group presented better 1-year outcomes than HFrEF group. The long-term prognosis and optimal medications for HFmrEF require further investigations. Electronic supplementary material The online version of this article (10.1186/s12872-019-1177-1) contains supplementary material, which is available to authorized users.

Background Elevated body mass index (BMI) is related with reduced mortality in various cardiovascular diseases. Hypothesis Gender‐specific association between BMI and mortality exists in atrial fibrillation (AF). Methods In this multicenter observational study with a mean follow‐up of 1 year, a total of 1991 AF patients were enrolled and divided into two groups based on the gender. The primary endpoint was all‐cause mortality while the secondary endpoints were defined as cardiovascular mortality, stroke, and major adverse events during 1‐year follow‐up. Cox regression was performed to identify the association between BMI and clinical outcomes according to gender. Results Female patients with AF tended to be older ( P = .027) and thinner ( P < .001) than male patients with AF. They were more likely to have heart failure, hyperthyroidism, and valvular AF (all P < .05), but less likely to have coronary artery disease and prior myocardial infarction (all P < .01). Multivariate analysis revealed that overweight (HR(95%CI): 0.55(0.41‐0.75), P < .001) and obese patients (HR(95%CI): 0.56(0.34‐0.94), P = .028) were associated with significant lower all‐cause mortality compared with normal weight patients for the entire cohort. Similar association between elevated BMI and reduced all‐cause mortality were only identified in female patients with AF (overweight vs normal weight: HR(95%CI): 0.43(0.27‐0.70); obesity vs normal weight: HR(95%CI): 0.46(0.22‐0.97)), but not in male patients with AF. Conclusion This study indicates that overweight and obesity were related with improved survival in patients with AF. The association between elevated BMI and reduced mortality was dependent on gender, which was only significant in female patients, rather than male patients.

Background The effect of type of atrial fibrillation (AF) on adverse outcomes in Chinese patients without oral anticoagulants (OAC) was controversial. Hypothesis The type of AF associated with adverse outcomes in Chinese patients without OAC. Methods A total of 1358 AF patients without OAC from a multicenter, prospective, observational study was included for analysis. Univariable and multivariable Cox regression models were utilized. Net reclassification improvement analysis was performed for the assessment of risk prediction models. Results There were 896(66%) patients enrolled with non‐paroxysmal AF (NPAF) and 462(34%) with paroxysmal AF (PAF). The median age was 70.9 ± 12.6 years, and 682 patients (50.2%) were female. During 1 year of follow‐up, 215(16.4%) patients died, and 107 (8.1%) patients experienced thromboembolic events. Compared with the PAF group, NPAF group had a notably higher incidence of all‐cause mortality (20.2% vs. 9.4%, p < .001), thromboembolism (10.5% vs. 3.8%, p < .001). After multivariable adjustment, NPAF was a strong predictor of thromboembolism (HR 2.594, 95%CI 1.534–4.386; p < .001), all‐cause death (HR 1.648, 95%CI 1.153–2.355; p = .006). Net reclassification improvement analysis indicated that the addition of NPAF to the CHA2DS2‐VASc score allowed an improvement of 0.37 in risk prediction for thromboembolic events (95% CI 0.21–0.53; p < .001). Conclusions In Chinese AF patients who were not on OAC, NPAF was an independent predictor of thromboembolism and mortality. The addition of NPAF to the CHA2DS2‐VASc score allowed an improvement in the accuracy of the prediction of thromboembolic events.