GATA3 promotes the autophagy and activation of hepatic stellate cell in hepatic fibrosis via regulating miR-370/HMGB1 pathway / GATA3 promueve la autofagia y la activación de la célula estrellada hepática en la fibrosis hepática a través de la regulación de la vía miR-370/HMGB1

Background Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. Methods ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-β1 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. Results CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagy-related proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3′-UTR. The promotion of GATA3 to TGF-β1-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. Conclusions This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF. (AU)

Introducción La fibrosis hepática (IC) es un resultado común del proceso de reparación de diversas enfermedades hepáticas crónicas. La activación de las células estrelladas hepáticas (HSC) es el vínculo central en la aparición de insuficiencia cardíaca. Métodos Se realizaron ELISA y análisis histológicos para detectar los cambios patológicos de los tejidos hepáticos. In vitro, las HSC se trataron con TGF-1 como modelo de células HF. La combinación de la proteína 3 de unión a GATA (GATA3) y el promotor del gen miR-370 se aseguró mediante el ensayo ChIP y el indicador de luciferasa. La autofagia se controló observando la formación de puntos GFP-LC3. La interacción entre miR-370 y la proteína de la caja 1 del grupo de alta movilidad (HMGB1) se verificó mediante el ensayo indicador de luciferasa. Resultados Los ratones con HF inducida por CCl4 exhibieron un aumento de ALT y AST, y daño severo y fibrosis de los tejidos hepáticos. GATA3 y HMGB1 estaban regulados positivamente, y miR-370 estaba regulado negativamente en ratones HF inducidos por CCl4 y HSC activadas. GATA3 mejoró la expresión de las proteínas relacionadas con la autofagia y los marcadores de activación en las HSC activadas. La inhibición de la autofagia revirtió parcialmente la activación de HSC inducida por GATA3 y la promoción de GATA3 a la fibrosis hepática. Además, GATA3 suprimió la expresión de miR-370 mediante la unión con su promotor y mejoró la expresión de HMGB1 en HSC. El aumento de miR-370 inhibió la expresión de HMGB1 al apuntar directamente a su ARNm 3 -UTR. La promoción de GATA3 a la autofagia y activación de las HSC inducidas por TGF-1 fue anulada por la regulación positiva de miR-370 o la eliminación de HMGB1. Conclusiones Este trabajo demuestra que GATA3 promueve la autofagia y la activación de las HSC mediante la regulación de la vía de señalización de miR-370/HMGB1, lo que contribuye para acelerar la HF... (AU)

Mesenchymal Stem Cell-Derived Exosomes in Various Chronic Liver Diseases: Hype or Hope?

Chronic liver conditions are associated with high mortality rates and have a large adverse effect on human well-being as well as a significant financial burden. Currently, the only effective treatment available for the effects of liver failure and cirrhosis resulting from the progression of several chronic liver diseases is liver transplantation carried out at the original location. This implies that developing novel and effective treatments is imperative. Regenerative medicine has long been associated with stem cell therapy. Mesenchymal stem cells (MSCs), a type of cell with great differentiation potential, have become the preferred source for stem cell therapy. According to recent studies, MSCs' paracrine products-rather than their capacity for differentiation-play a significant therapeutic effect. MSC exosomes, a type of extracellular vesicle (MSC-EV), came into view as the paracrine substances of MSCs. According to research, MSC exosomes can maintain tissue homeostasis, which is necessary for healthy tissue function. All tissues contain them, and they take part in a variety of biological activities that support cellular activity and tissue regeneration in order to preserve tissue homeostasis. The outcomes support the use of MSCs and the exosomes they produce as a therapeutic option for a range of diseases. This review provides a brief overview of the source of MSC-EVs and outlines their physiological roles and biochemical capabilities. The elucidation of the role of MSC-EVs in the recovery and repair of hepatic tissues, as well as their contribution to maintaining tissue homeostasis, is discussed in relation to different chronic liver diseases. This review aims to provide new insights into the unique roles that MSC-EVs play in the treatment of chronic liver diseases.

GATA3 promotes the autophagy and activation of hepatic stellate cell in hepatic fibrosis via regulating miR-370/HMGB1 pathway.

BACKGROUND: Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. METHODS: ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-ß1 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. RESULTS: CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagy-related proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3'-UTR. The promotion of GATA3 to TGF-ß1-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. CONCLUSIONS: This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF.