Bone marrow mesenchymal stem cell-derived exosomal microRNAs target PI3K/Akt signaling pathway to promote the activation of fibroblasts

BACKGROUND Fibroblast plays a major role in tendon-bone healing.Exosomes derived from bone marrow mesenchymal stem cells(BMSCs)can activate fibroblasts and promote tendon-bone healing via the contained microRNAs(miRNAs).However,the underlying mechanism is not comprehensively understood.Herein,this study aimed to identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets,and to verify their effects as well as mechanisms on fibroblasts.AIM To identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets and verify their effects as well as mechanisms on fibroblasts.METHODS BMSC-derived exosomal miRNAs data(GSE71241,GSE153752,and GSE85341)were downloaded from the Gene Expression Omnibus(GEO)database.The candidate miRNAs were obtained by the intersection of three data sets.TargetScan was used to predict potential target genes for the candidate miRNAs.Functional and pathway analyses were conducted using the Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)databases,respectively,by processing data with the Metascape.Highly interconnected genes in the protein-protein interaction(PPI)network were analyzed using Cytoscape software.Bromodeoxyuridine,wound healing assay,collagen contraction assay and the expression of COL I andα-smooth muscle actin positive were applied to investigate the cell proliferation,migration and collagen synthesis.Quantitative real-time reverse transcription polymerase chain reaction was applied to determine the cell fibroblastic,tenogenic,and chondrogenic potential.RESULTS Bioinformatics analyses found two BMSC-derived exosomal miRNAs,has-miR-144-3p and hasmiR-23b-3p,were overlapped in three GSE datasets.PPI network analysis and functional enrichment analyses in the GO and KEGG databases indicated that both miRNAs regulated the PI3K/Akt signaling pathway by targeting phosphatase and tensin homolog(PTEN).In vitro experiments confirmed that miR-144-3p and miR-23b-3p stimulated proliferation,migration and collagen synthesis of NIH3T3 fibroblasts.Interfering with PTEN affected the phosphorylation of Akt and thus activated fibroblasts.Inhibition of PTEN also promoted the fibroblastic,tenogenic,and chondrogenic potential of NIH3T3 fibroblasts.CONCLUSION BMSC-derived exosomes promote fibroblast activation possibly through the PTEN and PI3K/Akt signaling pathways,which may serve as potential targets to further promote tendon-bone healing.

Clinical Performance of Cell-Free Fetal DNA Testing for Fetal Aneuploidies and Subchromosomal Deletions/Duplications in a Cohort of 19,531 Pregnancies

Objective:We aim to assess the clinical performance of cell-free fetal DNA(cffDNA)testing for detecting common fetal aneuploidies as well as subchromosomal deletions/duplications and explore the pregnancy decisions in screen-positive cases.Methods:A cohort of 19,531 pregnant women was offered cffDNA testing for detection of trisomies 21,18,and 13(T21,T18,and T13);sex chromosome aneuploidies(SCAs);and subchromosomal deletions/duplications.Screen-positive cases were confirmed by karyotyping and single-nucleotide polymorphism array analysis.Results:A total of 47 cases failed the test.The overall screen-positive rate of chromosomal abnormalities was 1.07%(208/19,484),including 57 cases with T21,18 cases with T18,7 cases with T13,106 cases with SCAs,and 20 cases of subchromosomal deletions/duplications.Positive predictive values were 91.30%(42/46),38.46%(5/13),33.33%(2/6),41.33%(31/75),and 27.78%(5/18),respectively.There was no significant difference in the screening of fetal chromosomal aneuploidies in the high-risk group compared with the low-risk group(P>0.05).All of the pregnant women who had confirmed fetal T21,T18,or T13 terminated their pregnancies,except for a case of T13 mosaic,whereas 45.16%(14/31)of women with fetal SCAs continued their pregnancies.Furthermore,17 pregnant women with positive screens for T21,T18,or T13 without a subsequent diagnosis chose to terminate their pregnancy,whereas 29 of 31 women with SCAs chose to continue their pregnancies.Conclusions:CffDNA testing exhibited good screening accuracy for T21,T18,and T13 and also contributed to detecting fetal SCAs and subchromosomal deletions/duplications.Pregnant women with fetal 47,XXX or 47,XYY were more willing to terminate their pregnancy than those with fetal 45,X or 47,XXY.

Effectiveness of lifestyle intervention for hypertension in Shanghai communities: Results from the Shanghai Hypertension Detail Management Program

A community-based multi-center randomized controlled trial was conducted to evaluate the effectiveness of blood pressure control for hypertension patients in communities in urban Shanghai by integrated intervention.At present,patients(n=1395)from four communities have completed follow-up for one year,including the intervention group(n=921)and usual care group(n=474).The intervention programs included disease manage-ment by a care manager.Blood pressure of each patient was measured regularly.Compared with the control group,the net change of mean systolic blood pressure(SBP)was–6.75(95%CI:–7.79 to–5.71,P<0.001)mmHg,mean diastolic blood pressure(DBP)was–4.29(95%CI:–5.08 to–3.49,P<0.001)mmHg,and mean pulse pressure(PP)was–2.46(95%CI:–3.50 to–1.43,P<0.001)mmHg in the intervention group.The net change extent was larger in patients with regular pharmacological treatment than in those with irregular pharmacological treatment or non-pharmacological treat-ment.The measures of integrated intervention for hypertension patients in communities can lower signifi-cantly not only SBP and DBP,but also PP.It is suggested that measures of integrated intervention can decrease the risk of cardiovascular diseases in hypertension patients.