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In recent years, mesenchymal stem cells (MSCs)–derived extracellular vesicles (EVs) are emerging as a potential therapeutic agent for pulmonary hypertension (PH). However, the full realization of MSCs-derived EVs therapy has been hampered by the absence of standardization in MSCs culture and the challenges of industrial scale-up. The study was to exploit an alternative replacement for MSCs using currently commercialized stem cell lines for effective targeted PH therapy. ReNcell VM—a human neural stem cell line—has been utilized here as a reliable and easily adoptable source of EVs. We first demonstrated that ReNcell-derived EVs (ReNcell-EVs) pretreatment effectively prevented Su/Hx (SU5416/hypoxia)-induced PH in mice. Then for targeted therapy, we conjugated ReNcell-EVs with CAR (CARSKNKDC) peptide (CAR-EVs)—a peptide identified to specifically target hypertensive pulmonary arteries, by bio-orthogonal chemistry. Intravenous administration of CAR-EVs selectively targeted hypertensive pulmonary artery lesions especially pulmonary artery smooth muscle cells. Moreover, compared with unmodified ReNcell-EVs, CAR-EVs treatment significantly improved therapeutic effect in reversing Su/Hx-induced PH in mice. Mechanistically, ReNcell-EVs inhibited hypoxia-induced proliferation, migration, and phenotype switch of pulmonary artery smooth muscle cells, at least in part, via the delivery of its endogenous highly expressed miRNAs, let-7b-5p, miR-92b-3p, and miR-100-5p. In addition, we also found that ReNcell-EVs inhibited hypoxia-induced cell apoptosis and endothelial-mesenchymal transition in human microvascular endothelial cells. Taken together, our results provide an alternative to MSCs-derived EVs–based PH therapy via using ReNcell as a reliable source of EVs. Particularly, our CAR-conjugated EVs may serve as a novel drug carrier that enhances the specificity and efficiency of drug delivery for effective PH-targeted therapy.

Multi-organ fibrosis among end stage renal disease (ESRD) patients cannot be explained by uremia alone. Despite mitigation of thrombosis during hemodialysis (HD), subsequent platelet dysfunction and tissue dysregulation are less understood. We comprehensively profiled plasma and platelets from ESRD patients before and after HD to examine HD-modulation of platelets beyond thrombotic activation. Basal plasma levels of proteolytic regulators and fibrotic factors were elevated in ESRD patients compared to healthy controls, with isoform-specific changes during HD. Platelet lysate (PL) RNA transcripts for growth and coagulative factors were elevated post-HD, with upregulation correlated to HD vintage. Platelet secretome correlations to plasma factors reveal acutely induced pro-fibrotic platelet phenotypes in ESRD patients during HD characterized by preferentially enhanced proteolytic enzyme translation and secretion, platelet contribution to inflammatory response, and increasing platelet dysfunction with blood flow rate (BFR) and Vintage. Compensatory mechanisms of increased platelet growth factor synthesis with acute plasma matrix metalloproteinase (MMP) and tissue inhibitor of MMPs (TIMP) increases show short-term mode-switching between dialysis sessions leading to long-term pro-fibrotic bias. Chronic pro-fibrotic adaptation of platelet synthesis were observed through changes in differential secretory kinetics of heterogenous granule subtypes. We conclude that chronic and acute platelet responses to HD contribute to a pro-fibrotic milieu in ESRD.

Introduction Several Mendelian randomization studies have been conducted that identified multiple risk factors for Alzheimer's disease (AD). However, they typically focus on a few pre‐selected risk factors. Methods A two‐sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1037 risk factors/medical conditions and 31 drugs with the risk of late‐onset AD. To correct for multiple comparisons, the false discovery rate was set at

IntroductionSeveral Mendelian randomization studies have been conducted, which identified multiple risk factors for Alzheimer’s disease (AD). However, they typically focus on a few pre-selected risk factors.MethodsTwo-sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1,054 risk factors/medical conditions and 28 drugs with the risk of late- onset AD. To correct for multiple comparisons, the false discovery rate was set at <0.05.ResultsThere were strong evidence of a causal association between glioma risk, reduced trunk fat-free mass, lower education levels, lower intelligence and a higher risk of AD. For 28 investigated treatments (such as antihypertensive drugs), we found limited evidence for their associations.ConclusionMR found robust evidence of causal associations between glioma, trunk fat-free and AD. Our study also confirms that higher educational attainment and higher intelligence are associated with a reduced risk of AD.