By shaping T cell immunity, tolerogenic dendritic cells (tDCs) play critical roles in the induction of immune tolerance after transplantation. However, the role of long noncoding RNAs (lncRNAs) in the function and immune tolerance of dendritic cells (DCs) is largely unknown. Here, we found that the lncRNA MALAT1 is upregulated in the infiltrating cells of tolerized mice with cardiac allografts and activated DCs. Functionally, MALAT1 overexpression favored a switch in DCs toward a tolerant phenotype. Mechanistically, ectopic MALAT1 promoted dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) expression by functioning as an miR155 sponge, which is essential for the tolerogenic maintenance of DCs and the DC-SIGN-positive subset with more potent tolerogenic ability. The adoptive transfer of MALAT1-overexpressing DCs promoted cardiac allograft survival and protected from the development of experimental autoimmune myocarditis, accompanied with increasing antigen-specific regulatory T cells. Therefore, overexpressed MALAT1 induces tDCs and immune tolerance in heart transplantation and autoimmune disease by the miRNA-155/DC-SIGH/IL10 axis. This study highlights that the lncRNA MALAT1 is a novel tolerance regulator in immunity that has important implications in settings in which tDCs are preferred.

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Background/Aims: Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical arterial smooth muscle cells (HUASMCs) to a proliferative phenotype were examined. Methods: HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. Results: We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. Conclusion: Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis.

BackgroundMesenchymal stem cells (MSCs) are emerging as an extremely promising therapeutic agent for tissue repair. However, limitations exist such as the low numbers of MSCs obtained from donors, and the poor survival and function of donor cells. Omentin-1, a new fat depot-specific secretory adipokine, exerts proproliferation, prosurvival, and proangiogenic functions in certain cells via an Akt-dependent mechanism; however, little is known about the influence of omentin-1 on MSCs.MethodsMSCs were isolated from 60–80 g donor rats. Cell proliferation was assessed with CCK-8 and EdU assay. Cell cycle, apoptosis ratio, reactive oxygen species concentration, and mitochondrial membrane potential were detected by flow cytometry. Hoechst 33342 dye was used to assess morphological changes of apoptosis. Expression levels of Akt, FoxO3a, GSK-3β, and apoptosis- and cell cycle-associated proteins were detected by Western blotting. Tube formation assay was used to test the angiogenesis role of conditioned medium from MSCs in vitro. The cytokine secretion was assessed by ELISA.ResultsAfter treatment with omentin-1 (100–800 ng/ml), MSCs displayed a higher proliferative capacity with an increasing number of cells in the S and G2 phase of the cell cycle. Moreover, omentin-1 preconditioning for 1 h could protect MSCs against H2O2-induced apoptosis in a concentration-dependent manner. Furthermore, omentin-1 pretreatment reduced the excessive reactive oxygen species. Western blots revealed that increased Bcl-2 and decreased Bax appeared in MSCs after omentin-1 incubation, which inhibited the mitochondrial apoptosis pathways with evidence showing inhibition of caspase-3 cleavage and preservation of mitochondrial membrane potential. Omentin-1 could enhance angiogenic growth factor secretion and elevate the ability of MSCs to stimulate tube formation by human umbilical vein endothelial cells (HUVECs). Furthermore, omentin-1 enhanced Akt phosphorylation; however, blockade of the PI3K/Akt pathway with an inhibitor, LY294002 (20 μM), suppressed the above beneficial effects of omentin-1.ConclusionOmentin-1 can exert beneficial effects on MSCs by promoting proliferation, inhibiting apoptosis, increasing secretion of angiogenic cytokines, and enhancing the ability for stimulating tube formation by HUVECs via the PI3K/Akt signaling pathway. Thus, omentin-1 may be considered a candidate for optimizing MSC-based cell therapy.

BackgroundHormone level fluctuation across the menstrual cycle causes women to experience negative emotions and also affects their mood regulation and stress sensitivity. However, the stress reactivity and emotional variations in women with premenstrual syndrome (PMS), who are especially sensitive to the variations in hormone cycles, have not been explained.MethodsThe present study used an electroencephalogram (EEG) stress evaluation test, a physiology stress evaluation test, and the positive affect and negative affect scale (PANAS) to evaluate the stress reactivity pattern and emotional state of women with PMS.ResultsThe results showed that women with PMS had higher negative affect and lower positive affect compared with controls. Moreover, under stressful conditions, the women with PMS had a higher alpha activity and a lower respiration rate than the controls. The differences in stress reactivity and emotional states between women with PMS and controls were based on a covariant analysis with menstrual cycle (luteal and follicular phases) as the covariate.ConclusionThe results demonstrated that, compared with controls, women suffering from PMS have a continuous abnormality in emotional state and stress reactivity, which was independent of the menstrual cycle.