The antifibrotic potential of IMT504: modulation of GLAST + Wnt1 + bone marrow stromal progenitors and hepatic microenvironment.

BACKGROUND: The immunomodulatory oligodeoxynucleotide (ODN) IMT504 might harbor antifibrotic properties within the liver. METHODS: Fibrosis models were induced in mice through thioacetamide (TAA) administration and bile-duct ligation. Cre-loxP mice were utilized to identify GLAST + Wnt1 + bone marrow stromal progenitors (BMSPs) and to examine their contribution with cells in the liver. In vivo and in vitro assays; flow-cytometry, immunohistochemistry, and qPCR were conducted. RESULTS: IMT504 demonstrated significant inhibition of liver fibrogenesis progression and reversal of established fibrosis. Early responses to IMT504 involved the suppression of profibrogenic and proinflammatory markers, coupled with an augmentation of hepatocyte proliferation. Additionally, this ODN stimulated the proliferation and mobilization of GLAST + Wnt1 + BMSPs, likely amplifying their contribution with endothelial- and hepatocytes-like cells. Moreover, IMT504 significantly modulated the expression levels of Wnt ligands and signaling pathway/target genes specifically within GLAST + Wnt1 + BMSPs, with minimal impact on other BMSPs. Intriguingly, both IMT504 and conditioned media from IMT504-pre-treated GLAST + Wnt1 + BMSPs shifted the phenotype of fibrotic macrophages, hepatic stellate cells, and hepatocytes, consistent with the potent antifibrotic effects observed. CONCLUSION: In summary, our findings identify IMT504 as a promising candidate molecule with potent antifibrotic properties, operating through both direct and indirect mechanisms, including the activation of GLAST + Wnt1 + BMSPs.

Hepatokines and adipokines in NASH-related hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors - in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin - for detection or even as therapeutic targets in NAFLD-related HCC.

Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies.

Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells (MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise, it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles (EVs). EVs contain proteins, lipids and nucleic acids (DNA, mRNA, miRNA, lncRNA) from the cell of origin, allowing for intercellular communication. Recently, different studies have demonstrated that MSC-derived EVs could reproduce, at least in part, the biological effects obtained by MSC-based therapies. Moreover, due to EVs' stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration, the role of EVs in liver physiopathology and the potential of MSCderived EVs as intercellular mediators and therapeutic tools in liver diseases.