TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis: Updated

Abstract

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

Synergy of Phospholipid—Drug Formulations Significantly Deactivates Profibrogenic Human Hepatic Stellate Cells

“…As previously described (Scheme 1), in our study cells were treated with TGF-β1 and Rol + PA in order to thoroughly investigate the progression and regression of LX-2 cells' fibrogenic feature. The results were in agreement with the expected behavior of activated and quiescent-like HSCs, respectively [39,40,43,45].…”

“…After cell seeding, the CM from seeded LX-2 cells was discarded and the cells were rinsed once with phosphate-buffered saline (PBS). Treatments of LX-2 cells in microtiter plates were then performed directly on naïve LX-2 cells or after a further activation of LX-2 cells (perpetuated LX-2 cells; pLX-2 cells) obtained with TGF-β 1 [12,39,40] . For the direct treatment, the formulations were mixed with EM and LX-2 cells were incubated with this solution for 24 h, as described below.…”

“…TGF-β 1 was discarded, and the cells were rinsed once with PBS and then treated as described below. TGF-β 1 (10 ng/mL) was also used as control to induce fibrogenesis in the direct treatment starting from naïve LX-2 cells [12,39,40] . A graphical representation of the experimental approach is depicted in Scheme 1.…”

Preventive effects of Ophiocordyceps sinensis mycelium on the liver fibrosis induced by thioacetamide

“…The TGF‐β relative pathway is a classic fibrotic signaling cascade in various tissues, and it has been proved to be a necessary factor in the HSC activation . Taylor indicated that pro‐ and activated‐TGF‐β molecules are released from ECM via immune cells, such as T‐cell, Kupffer cell and so forth.…”

“…In addition, the less marker protein of hepatic macrophage, The TGF-b relative pathway is a classic fibrotic signaling cascade in various tissues, and it has been proved to be a necessary factor in the HSC activation. 27 Respectively, the scales were shown in 20 (3100, first column in left hand) and 100 lm (3400, second column), respectively. Slides were stained with primary antibody and hematoxylin; moreover, the primary antibody was absent in NC (Negative control) group, and the signals were amplified with ABC system.…”