BMSCs alleviate liver cirrhosis by regulating Fstl1/Wnt/ß-Catenin signaling pathway.

Researchers have shown that bone mesenchymal stem cells (BMSCs) can alleviate the progression of liver cirrhosis; however, it is unclear how exactly BMSCs function to cure liver disease. In this study, we used bioinformatics methods to assess differentially expressed genes (DEGs) in liver cirrhosis and found a significantly upregulated gene, Fstl1, in liver cirrhosis. In vivo and in vitro experiments showed that compared with those in the disease model group, the mRNA, and protein expression levels of Fstl1 were significantly reduced after BMSCs treatment, and the ß-Catenin protein level was also significantly reduced after BMSCs treatment. Subsequently, we downregulated Fstl1 in activated hepatic stellate cells (HSCs) and found that Wnt and ß-Catenin protein expression levels also decreased. Finally, we found that in BMSCs-treated activated HSCs, overexpression of Fstl1 reversed the inhibitory effect of BMSCs on the Wnt/ß-Catenin signaling pathway to a certain extent. In summary, our results show that BMSCs can inhibit Wnt/ß-Catenin signaling pathway activation by downregulating the protein expression level of Fstl1, thus alleviating cirrhosis. Therefore, targeted regulation of Fstl1 may provide a new therapeutic strategy for the progression of liver cirrhosis.

From Phenomenon to Essence: A Newly Involved lncRNA Kcnq1ot1 Protective Mechanism of Bone Marrow Mesenchymal Stromal Cells in Liver Cirrhosis.

Bone marrow mesenchymal stromal cells (BMSCs) have a protective effect against liver cirrhosis. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of liver cirrhosis. Therefore, it is aimed to clarify the lncRNA Kcnq1ot1 involved protective mechanism of BMSCs in liver cirrhosis. This study found that BMSCs treatment attenuates CCl4 -induced liver cirrhosis in mice. Additionally, the expression of lncRNA Kcnq1ot1 is upregulated in human and mouse liver cirrhosis tissues, in addition to TGF-ß1-treated LX2 cells and JS1 cells. The expression of Kcnq1ot1 in liver cirrhosis is reversed with BMSCs treatment. The knockdown of Kcnq1ot1 alleviated liver cirrhosis both in vivo and in vitro. Fluorescence in situ hybridization (FISH) confirms that Kcnq1ot1 is mainly distributed in the cytoplasm of JS1 cells. It is predicted that miR-374-3p can directly bind with lncRNA Kcnq1ot1 and Fstl1, which is verified via luciferase activity assay. The inhibition of miR-374-3p or the overexpression of Fstl1 can attenuate the effect of Kcnq1ot1 knockdown. In addition, the transcription factor Creb3l1 is upregulated during JS1 cells activation. Moreover, Creb3l1 can directly bind to the Kcnq1ot1 promoter and positively regulate its transcription. In conclusion, BMSCs alleviate liver cirrhosis by modulating the Creb3l1/lncRNA Kcnq1ot1/miR-374-3p/Fstl1 signaling pathway.

Exosomes Derived from BMMSCs Mitigate the Hepatic Fibrosis via Anti-Pyroptosis Pathway in a Cirrhosis Model.

Researchers increasingly report the therapeutic effect of exosomes derived from rat bone marrow mesenchymal stem cells (Exos-rBMMSC) on liver disease, while the optimal dose of Exos-rBMMSC in liver cirrhotic treatment has not been reported. In this study, we aimed to explore the efficacy and dose of Exos-rBMMSC in a hepatic cirrhosis rat model. The therapeutic effects of a low dose, medium dose and high dose of Exos-rBMMSC were assessed by liver function tests and histopathology. After four-weeks of Exos-rBMMSC therapy, pyroptosis-related expression levels in the medium dose and the high dose Exos-rBMMSC groups were significantly decreased compared to those in the liver cirrhosis group (p < 0.05). The hepatic function assay and histopathology results showed significant improvement in the medium dose and the high dose Exos-rBMMSCs groups. The localization of PKH67-labeled Exos-rBMMSC was verified microscopically, and these particles were coexpressed with the PCNA, NLRP3, GSDMD and Caspase-1. Our results demonstrated that Exos-rBMMSC accelerated hepatocyte proliferation and relieved liver fibrosis by restraining hepatocyte pyroptosis. More importantly, we confirmed that the high dose of Exos-rBMMSC may be the optimal dose for liver cirrhosis, which is conducive to the application of Exos-rBMMSC as a promising cell-free strategy.

Hair follicle-MSC-derived small extracellular vesicles as a novel remedy for acute pancreatitis.

BACKGROUND: Hair follicle-derived mesenchymal stem cell (HF-MSC)-based therapies protect against acute pancreatitis (AP). However, accumulating evidence suggests that MSC-based therapy mainly involves the secretion of MSC-derived small extracellular vesicles (MSC-sEVs) through paracrine effects. Thus, the present research investigated the therapeutic effect of HF-MSC-sEVs in AP and the underlying mechanisms. METHODS: SEVs were purified from cultured HF-MSC supernatant. The effects of sEVs in vitro were analyzed on caerulein-simulated pancreatic acinar cells (PACs). The therapeutic potential of sEVs in vivo was examined in a caerulein-induced AP model. The organ distribution of sEVs in mice was determined by near-infrared fluorescence (NIRF) imaging. Serum specimens and pancreatic tissues were collected to analyze the inhibition of inflammation and pyroptosis in vivo, as well as the appropriate infusion route: intraperitoneal (i.p.) or intravenous (i.v.) injection. RESULTS: HF-MSC-sEVs were taken up by PACs and improved cell viability in vitro. In vivo, sEVs were abundant in the pancreas, and the indicators of pancreatitis, including amylase, lipase, the inflammatory response, myeloperoxidase (MPO) expression and histopathology scores, in sEV-treated mice were markedly improved compared with those in the AP group, especially via tail vein injection. Furthermore, we revealed that sEVs observably downregulated the levels of crucial pyroptosis proteins in both PACs and AP tissue. CONCLUSIONS: We innovatively demonstrated that HF-MSC-sEVs could alleviate inflammation and pyroptosis in PACs in AP, suggesting a refreshing cell-free remedy for AP.

Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis.

AIMS: Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M1 (pro-inflammatory) and M2 (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis. MAIN METHODS: Utilized CCl4 to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/Erk/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis. KEY FINDINGS: During CCl4-induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M1-KCs, and it increased the number of M2-KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M2/M1-KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M2-KCs to M1-KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M1 to M2. The cytokine exerted these effects by activating the STAT3 pathway while suppressing Erk1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M2-KCs during liver fibrogenesis. SIGNIFICANCE: IL-22 regulates the STAT3/Erk/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.

Crosstalk network among multiple inflammatory mediators in liver fibrosis.

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.