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BACKGROUND: Mesenchymal stem cells (MSCs) have been used in liver transplantation and have certain effects in alleviating liver ischemia-reperfusion injury (IRI) and regulating immune rejection. However, some studies have indicated that the effects of MSCs are not very significant. Therefore, approaches that enable MSCs to exert significant and stable therapeutic effects are worth further study. AIM: To enhance the therapeutic potential of human menstrual blood-derived stromal cells (MenSCs) in the mouse liver ischemia-reperfusion (I/R) model via interferon-γ (IFN-γ) priming. METHODS: Apoptosis was analyzed by flow cytometry to evaluate the safety of IFN-γ priming, and indoleamine 2,3-dioxygenase (IDO) levels were measured by quantitative real-time reverse transcription polymerase chain reaction, western blotting, and ELISA to evaluate the efficacy of IFN-γ priming. In vivo, the liver I/R model was established in male C57/BL mice, hematoxylin and eosin and TUNEL staining was performed and serum liver enzyme levels were measured to assess the degree of liver injury, and regulatory T cell (Treg) numbers in spleens were determined by flow cytometry to assess immune tolerance potential. Metabolomics analysis was conducted to elucidate the potential mechanism underlying the regulatory effects of primed MenSCs. In vitro, we established a hypoxia/reoxygenation (H/R) model and analyzed apoptosis by flow cytometry to investigate the mechanism through which primed MenSCs inhibit apoptosis. Transmission electron microscopy, western blotting, and immunofluorescence were used to analyze autophagy levels. RESULTS: IFN-γ-primed MenSCs secreted higher levels of IDO, attenuated liver injury, and increased Treg numbers in the mouse spleens to greater degrees than untreated MenSCs. Metabolomics and autophagy analyses proved that primed MenSCs more strongly induced autophagy in the mouse livers. In the H/R model, autophagy inhibitors increased the level of H/R-induced apoptosis, indicating that autophagy exerted protective effects. In addition, primed MenSCs decreased the level of H/R-induced apoptosis via IDO and autophagy. Further rescue experiments proved that IDO enhanced the protective autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway and activating the AMPK pathway. CONCLUSION: IFN-γ-primed MenSCs exerted better therapeutic effects in the liver I/R model by secreting higher IDO levels. MenSCs and IDO activated the AMPK-mTOR-autophagy axis to reduce IRI, and IDO increased Treg numbers in the spleen and enhanced the MenSC-mediated induction of immune tolerance. Our study suggests that IFN-γ-primed MenSCs may be a novel and superior MSC product for liver transplantation in the future.
RESUMO
OBJECTIVE: To study the changes and clinical significance of amplitude-integrated electroencephalography (aEEG) in preterm infants with bronchopulmonary dysplasia (BPD). METHODS: A total of 156 preterm infants with a gestational age of ≤ 32+6 weeks who were diagnosed with BPD were enrolled as the BPD group, and 156 preterm infants without BPD who were hospitalized during the same period of time were enrolled as the control group. The aEEG scoring system for preterm infants was used to compare aEEG results between the two groups during hospitalization. A stratified analysis was conducted based on the examination time (at the corrected gestational age of ≤ 28+6 weeks, 29-30+6 weeks, 31-32+6 weeks, 33-34+6 weeks, 35-36+6 weeks, and 37-38+6 weeks). RESULTS: Compared with the non-BPD group, the BPD group had a significantly lower total aEEG score at the corrected gestational age of 33-34+6 weeks (P < 0.001). The mild BPD group had a significantly lower total aEEG score than the non-BPD group at the corrected gestational age of 33-34+6 weeks (P < 0.05); the moderate BPD group had a significantly lower total aEEG score than the non-BPD group at the corrected gestational ages of 31-32+6 weeks, 33-34+6 weeks, and 35-36+6 weeks (P < 0.05); the severe BPD group had a significantly lower total aEEG score than the non-BPD group at all corrected gestational ages except ≤ 28+6 weeks and 29-30+6 weeks (P < 0.05). CONCLUSIONS: Preterm infants with BPD (especially moderate to severe BPD) have a lower aEEG score than those without BPD, suggesting that their nervous system development may lag behind that of non-BPD preterm infants with the same gestational age. Therefore, early nervous system evaluation and intervention are necessary for preterm infants with BPD.