Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1b (IL-1b) is one of the most important inflammatory mediators, growing evidence indicates that IL-1b signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1b signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1b-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1b-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1b-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1b-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1b-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.

Mesenchymal stem cells (MSCs) are attractive candidates for clinical therapeutic applications. Recent studies indicate MSCs express active Toll-like receptors (TLRs), but their effect on MSCs and the underlying mechanisms remain unclear. In this study, we found that, after treating human umbilical cord MSCs with various TLR ligands, only TLR3 ligand, poly(I:C), could significantly increase the expression of cyclooxygenase-2 (COX-2). Furthermore, poly(I:C) could enhance MSCs' anti-inflammatory effect on macrophages. Next, we focused on the regulatory roles of microRNAs (miRNAs) in the process of poly(I:C) activating MSCs. Our experiments indicated that miR-143 expression was significantly decreased in MSCs with poly(I:C) treatment, and the expression level of miR-143 could regulate the effect of poly(I:C) on MSCs' immunosuppressive function. Subsequent results showed that the reporter genes with putative miR-143 binding sites from the transforming growth factor-b-activated kinase-1 (TAK1) and COX-2 3 0 untranslated regions were downregulated in the presence of miR-143. In addition, mRNA and protein expression of TAK1 and COX-2 in MSCs was also downregulated with miR-143 overexpression, suggesting that TAK1 and COX-2 are target genes of miR-143 in MSCs. Consistent with miR-143 overexpression, TAK1 interference also attenuated MSCs' immunosuppressive function enhanced by poly(I:C). Additionally, it was shown that TLR3-activated MSCs could improve survival in cecal ligation and puncture (CLP)-induced sepsis, while miR-143 overexpression reduced the effectiveness of this therapy. These results proved that poly(I:C) improved the immunosuppressive abilities of MSCs, revealed the regulatory role of miRNAs in the process, and may provide an opportunity for potential novel therapies for sepsis. STEM CELLS 2014;32:521-533

BackgroundStanniocalcin-1(STC-1) is up-regulated in several cancers including gastric cancer. Evidences suggest that STC-1 is associated with carcinogenesis and angiogenic process. However, it is unclear on the exact role for STC-1 in inducing angiogenesis and tumorigeneisis.MethodBGC/STC cells (high-expression of STC-1) and BGC/shSTC cells (low- expression of STC-1) were constructed to investigate the effect of STC-1 on the xenograft tumor growth and angiogenesis in vitro and in vivo. ELISA assay was used to detect the expression of vascular endothelial growth factor (VEGF) in the supernatants. Neutralizing antibody was used to inhibit VEGF expression in supernatants. The expression of phosphorylated -PKCβII, phosphorylated -ERK1/2 and phosphorylated -P38 in the BGC treated with STC-1protein was detected by western blot.ResultsSTC-1 could promote angiogenesis in vitro and in vivo, and the angiogenesis was consistent with VEGF expression in vitro. Inhibition of VEGF expression in supernatants with neutralizing antibody markedly abolished angiogenesis induced by STC-1 in vitro. The process of STC-1-regulated VEGF expression was mediated via PKCβII and ERK1/2.ConclusionsSTC-1 promotes the expression of VEGF depended on the activation of PKCβII and ERK1/2 pathways. VEGF subsequently enhances tumor angiogenesis which in turn promotes the gastric tumor growth.

In the present study, we first prove that progesterone can regulate NK cells via GR. It is valuable for further understanding the role of uNK in progesterone regulated gestation process.

Epithelial-mesenchymal transition (EMT) plays a specific role in the migration of tumor cells. Both estrogen and midkine (MK) have been thought to be important factors in promoting the progression of non-small-cell lung cancer (NSCLC) and can enhance EMT. Some evidence indicated the correlation between estradiol (E2) and MK, but the precise mechanism on their interreaction is unknown. Here, we try to clarify whether and how E2 regulates MK expression to promote EMT. We found that E2 increased MK mRNA expression in lung adenocarcinoma cells LTEP-a2 and A549 in a time-dependent manner. E2-induced MK expression was inhibited by the estrogen receptor (ER) antagonist ICI 182,780 and tamoxifen but not by phosphoinositide-3 kinase and MAPK inhibitors, suggesting a genomic mechanism of E2 on the regulation of MK transcription. Moreover, luciferase reporter and chromatin immunoprecipitation assays exhibited that E2 induced ERβ recruitment to the estrogen response element in the MK promoter. Small interfering RNA to ERα and ERβ revealed that ERβ mainly mediated E2-induced MK transcription. Interestingly, E2 enhanced MK expression in accordance with increase of EMT, whereas knockdown of MK could block EMT under E2 stimulation. Importantly, through analyzing lung adenocarcinoma tissues, there was indeed a correlation among levels of E2, MK, and EMT-related protein expression. Taken together, we reported a previously unrecognized mechanism on E2 in the regulation of MK expression and proved that MK plays a pivotal role in progression of E2-regulated EMT.

The activation of IFN-α signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Many studies suggest that estrogens are closely related to the gender difference in the prevalence of SLE. However, the underlying mechanism of the interaction between estrogens and the activation of IFN-α signaling in SLE B cells remains incompletely understood. In the present study, we first found that healthy female mice showed an up-regulated type I IFN-induced gene signature in B cells compared with age-matched male mice, and an in vivo study revealed that the gender difference was related to 17β-estradiol. Moreover, we found that 17β-estradiol could enhance the activation of IFN-α signaling in an ERα-dependent manner by down-regulating the expression of three microRNAs, including let-7e-5p, miR-98-5p and miR-145a-5p. These microRNAs could target the 3'UTR of the IKKε-encoding gene IKBKE directly and regulate the expression of IKKε, which can promote the activation of IFN-α signaling. In addition, compared with age-matched male mice, female mice showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p in B cells. Moreover, peripheral blood mononuclear cells from women showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p compared with those from age-matched men. These data suggest that 17β-estradiol amplifies the activation of IFN-α signaling in B cells via IKKε by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p. Our findings may provide a new perspective for understanding the mechanism underlying the gender difference in the prevalence of SLE.

In humans, a subset of placental cytotrophoblasts (CTBs) invades the uterus and its vasculature, anchoring the pregnancy and ensuring adequate blood flow to the fetus. Appropriate depth is critical. Shallow invasion increases the risk of pregnancy complications, e.g., severe preeclampsia. Overly deep invasion, the hallmark of placenta accreta spectrum (PAS), increases the risk of preterm delivery, hemorrhage, and death. Previously a rare condition, the incidence of PAS has increased to 1:731 pregnancies, likely due to the rise in uterine surgeries (e.g., Cesarean sections). CTBs track along scars deep into the myometrium and beyond. Here we compared the global gene expression patterns of CTBs from PAS cases to gestational age-matched control cells that invaded to the normal depth from preterm birth (PTB) deliveries. The messenger RNA (mRNA) encoding the guanine nucleotide exchange factor,DOCK4, mutations of which promote cancer cell invasion and angiogenesis, was the most highly up-regulated molecule in PAS samples. Overexpression ofDOCK4increased CTB invasiveness, consistent with the PAS phenotype. Also, this analysis identified other genes with significantly altered expression in this disorder, potential biomarkers. These data suggest that CTBs from PAS cases up-regulate a cancer-like proinvasion mechanism, suggesting molecular as well as phenotypic similarities in the two pathologies.

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