Hypoxia enhances anti-fibrotic properties of extracellular vesicles derived from hiPSCs via the miR302b-3p/TGFβ/SMAD2 axis

Abstract Background Cardiac fibrosis is one of the top killers among fibrotic diseases and continues to be a global unaddressed health problem. The lack of effective treatment combined with the considerable socioeconomic burden highlights the urgent need for innovative therapeutic options. Here, we evaluated the anti-fibrotic properties of extracellular vesicles (EVs) derived from human induced pluripotent stem cells (hiPSCs) that were cultured under various oxygen concentrations. Methods EVs were isolated from three hiPSC lines cultured under normoxia (21% O2; EV-N) or reduced oxygen concentration (hypoxia): 3% O2 (EV-H3) or 5% O2 (EV-H5). The anti-fibrotic activity of EVs was tested in an in vitro model of cardiac fibrosis, followed by a detailed investigation of the underlying molecular mechanisms. Sequencing of EV miRNAs combined with bioinformatics analysis was conducted and a selected miRNA was validated using a miRNA mimic and inhibitor. Finally, EVs were tested in a mouse model of angiotensin II-induced cardiac fibrosis. Results We provide evidence that an oxygen concentration of 5% enhances the anti-fibrotic effects of hiPS-EVs. These EVs were more effective in reducing pro-fibrotic markers in activated human cardiac fibroblasts, when compared to EV-N or EV-H3. We show that EV-H5 act through the canonical TGFβ/SMAD pathway, primarily via miR-302b-3p, which is the most abundant miRNA in EV-H5. Our results show that EV-H5 not only target transcripts of several profibrotic genes, including SMAD2 and TGFBR2, but also reduce the stiffness of activated fibroblasts. In a mouse model of heart fibrosis, EV-H5 outperformed EV-N in suppressing the inflammatory response in the host and by attenuating collagen deposition and reducing pro-fibrotic markers in cardiac tissue. Conclusions In this work, we provide evidence of superior anti-fibrotic properties of EV-H5 over EV-N or EV-H3. Our study uncovers that fine regulation of oxygen concentration in the cellular environment may enhance the anti-fibrotic effects of hiPS-EVs, which has great potential to be applied for heart regeneration. Graphical Abstrac

Clinical guidelines for postpartum women and infants in primary care–a systematic review

Background: While many women and infants have an uneventful course during the postpartum period, others experience significant morbidity. Effective postpartum care in the community can prevent short, medium and long-term consequences of unrecognised and poorly managed problems. The use of rigorously developed, evidence-based guidelines has the potential to improve patient care, impact on policy and ensure consistency of care across health sectors. This study aims to compare the scope and content, and assess the quality of clinical guidelines about routine postpartum care in primary care. Methods: PubMed, the National Guideline Clearing House, Google, Google Scholar and relevant college websites were searched for relevant guidelines. All guidelines regarding routine postpartum care published in English between 2002 and 2012 were considered and screened using explicit selection criteria. The scope and recommendations contained in the guidelines were compared and the quality of the guidelines was independently assessed by two authors using the AGREE II instrument. Results: Six guidelines from Australia (2), the United Kingdom (UK) (3) and the United States of America (USA) (1), were included. The scope of the guidelines varied greatly. However, guideline recommendations were generally consistent except for the use of the Edinburgh Postnatal Depression Scale for mood disorder screening and the suggested time of routine visits. Some recommendations lacked evidence to support them, and levels or grades of evidence varied between guidelines. The quality of most guidelines was adequate. Of the six AGREE II domains, applicability and editorial independence scored the lowest, and scope, purpose and clarity of presentation scored the highest. Conclusions: Only one guideline provided comprehensive recommendations for the care of postpartum women and their infants. As well as considering the need for region specific guidelines, further research is needed to strengthen the evidence supporting recommendations made within guidelines. Further improvement in the editorial independence and applicability domains of the AGREE ll criteria would strengthen the quality of the guidelines