Key genes associated with non-alcoholic fatty liver disease and hepatocellular carcinoma with metabolic risk factors.

Background: Hepatocellular carcinoma (HCC) has become the world's primary cause of cancer death. Obesity, hyperglycemia, and dyslipidemia are all illnesses that are part of the metabolic syndrome. In recent years, this risk factor has become increasingly recognized as a contributing factor to HCC. Around the world, non-alcoholic fatty liver disease (NAFLD) is on the rise, especially in western countries. In the past, the exact pathogenesis of NAFLD that progressed to metabolic risk factors (MFRs)-associated HCC has not been fully understood. Methods: Two groups of the GEO dataset (including normal/NAFLD and HCC with MFRs) were used to analyze differential expression. Differentially expressed genes of HCC were verified by overlapping in TCGA. In addition, functional enrichment analysis, modular analysis, Receiver Operating Characteristic (ROC) analysis, LASSO analysis, and Genes with key survival characteristics were analyzed. Results: We identified six hub genes (FABP5, SCD, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN) that may be closely related to NAFLD and HCC with MFRs. We constructed survival and prognosis gene markers based on FABP5, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN.This gene signature has shown good diagnostic accuracy in both NAFLD and HCC and in predicting HCC overall survival rates. Conclusion: As a result of the findings of this study, there is some guiding significance for the diagnosis and treatment of liver disease associated with NAFLD progression.

Short-Term Clinical Response and Changes in the Fecal Microbiota and Metabolite Levels in Patients with Crohn's Disease After Stem Cell Infusions.

Recent studies have shown a close relationship between the gut microbiota and Crohn's disease (CD). This study aimed to determine whether mesenchymal stem cell (MSC) treatment alters the gut microbiota and fecal metabolite pathways and to establish the relationship between the gut microbiota and fecal metabolites. Patients with refractory CD were enrolled and received 8 intravenous infusions of MSCs at a dose of 1.0 × 106 cells/kg. The MSC efficacy and safety were evaluated. Fecal samples were collected, and their microbiomes were analyzed by 16S rDNA sequencing. The fecal metabolites at baseline and after 4 and 8 MSC infusions were identified by liquid chromatography-mass spectrometry (LC--MS). A bioinformatics analysis was conducted using the sequencing data. No serious adverse effects were observed. The clinical symptoms and signs of patients with CD were substantially relieved after 8 MSC infusions, as revealed by changes in weight, the CD activity index (CDAI) score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). Endoscopic improvement was observed in 2 patients. A comparison of the gut microbiome after 8 MSC treatments with that at baseline showed that the genus Cetobacterium was significantly enriched. Linoleic acid was depleted after 8 MSC treatments. A possible link between the altered Cetobacterium abundance and linoleic acid metabolite levels was observed in patients with CD who received MSCs. This study enabled an understanding of both the gut microbiota response and bacterial metabolites to obtain more information about host-gut microbiota metabolic interactions in the short-term response to MSC treatment.

CCR2-overexpressing mesenchymal stem cells targeting damaged liver enhance recovery of acute liver failure.

BACKGROUND: Mesenchymal stem cell (MSC) transplantation is emerging as a promising cell therapeutic strategy in acute liver failure (ALF) clinical research. The potency of MSCs to migrate and engraft into targeted lesions could largely determine their clinical efficacy, in which chemokine/receptor axes play a crucial role. Unfortunately, the downregulation of chemokine receptors expression after in vitro expansion results in a poor homing capacity of MSCs. METHODS: By evaluating the chemokine expression profile in the liver of ALF patients and ALF mice, we found that CCL2 expression was highly upregulated in damaged livers, while the corresponding receptor, CCR2, was lacking in cultured MSCs. Thus, we genetically modified MSCs to overexpress CCR2 and investigated the targeted homing capacity and treatment efficacy of MSCCCR2 compared to those of the MSCvector control. RESULTS: In vivo and ex vivo near-infrared fluorescence imaging showed that MSCCCR2 rapidly migrated and localized to injured livers in remarkably greater numbers following systemic infusion, and these cells were retained in liver lesions for a longer time than MSCvector. Furthermore, MSCCCR2 exhibited significantly enhanced efficacy in the treatment of ALF in mice, which was indicated by a dramatically improved survival rate, the alleviation of liver injury with reduced inflammatory infiltration and hepatic apoptosis, and the promotion of liver regeneration. CONCLUSIONS: Altogether, these results indicate that CCR2 overexpression enhances the targeted migration of MSCs to damaged livers, improves their treatment effect, and may provide a novel strategy for improving the efficacy of cell therapy for ALF.

Human umbilical cord-derived mesenchymal stem cells ameliorate experimental colitis by normalizing the gut microbiota.

BACKGROUND: Crohn's disease (CD) is a chronic non-specific inflammatory bowel disease. Current CD therapeutics cannot fundamentally change the natural course of CD. Therefore, it is of great significance to find new treatment strategies for CD. Preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach. However, the mechanism by which MSCs alleviate CD and how MSCs affect gut microbes are still unclear and need further elucidation. METHODS: We used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis in mice and analysed the microbiota in faecal samples from the control group, the TNBS group and the TNBS + MSC group with faecal 16S rDNA sequencing. Subsequent analyses of alpha and beta diversity were all performed based on the rarified data. PICRUStII analysis was performed on the 16S rRNA gene sequences to infer the gut microbiome functions. RESULTS: MSC Treatment improved TNBS-induced colitis by increasing survival rates and relieving symptoms. A distinct bacterial signature was found in the TNBS group that differed from the TNBS + MSC group and controls. MSCs prevented gut microbiota dysbiosis, including increasing α-diversity and the amount of Bacteroidetes Firmicutes and Tenericutes at the phylum level and decreasing the amount of Proteobacteria at the phylum level. MSCs alleviated the increased activities of sulphur and riboflavin metabolism. Meanwhile some metabolic pathways such as biosynthesis of amino acids lysine biosynthesis sphingolipid metabolism and secondary bile acid biosynthesis were decreased in the TNBS group compared with the control group and the TNBS + MSC group CONCLUSIONS: Overall, our findings preliminarily confirmed that colitis in mice is closely related to microbial and metabolic dysbiosis. MSC treatment could modulate the dysregulated metabolism pathways in mice with colitis, restoring the abnormal microbiota function to that of the normal control group. This study provides insight into specific intestinal microbiota and metabolism pathways linked with MSC treatment, suggesting a new approach to the treatment of CD.

An Injectable Epigenetic Autophagic Modulatory Hydrogel for Boosting Umbilical Cord Blood NK Cell Therapy Prevents Postsurgical Relapse of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.

Injectable adhesive hemostatic gel with tumor acidity neutralizer and neutrophil extracellular traps lyase for enhancing adoptive NK cell therapy prevents post-resection recurrence of hepatocellular carcinoma.

Post-resection recurrence remains an intractable problem in hepatocellular carcinoma (HCC) management. Natural killer (NK) cell infusion is considered as a promising cancer therapy, but acidic tumor microenvironment (TME) and neutrophil extracellular traps (NETs) greatly counteract its efficacy. Recently, polymer hydrogels have aroused much interest in tumor combination therapy, since they load and controllably release therapeutic agents with high bioavailability and low systemic toxicity. Therefore, a biocompatible hydrogel with tumor acidity neutralizer and NETs lyase may show promise for enhancing NK infusion to prevent post-resection HCC recurrence. Herein, a dual pH-responsive hydrogel with tumor acidity neutralizer (mesoporous bioactive glass nanoparticles) and NETs lyase (Deoxyribonuclease I, DNase I) is developed and used in combination with NK cell infusion for preventing post-resection HCC recurrence. The hydrogel can be injected to surgical margin and form an adhesive gel with a rapid hemostasis. Besides, it neutralizes tumor acidity to reduce tumor infiltration of immunosuppressive cells, and releases DNase I in a pH-responsive manner to degrade NETs. Moreover, this combination therapy significantly enhances NK cell infusion to combat post-surgical HCC recurrence without systemic toxicity. This study provides proof of concept that combination of NK cell adoptive therapy and hydrogel-based delivery system can successfully prevent post-resection HCC recurrence.