Autophagy and Exosomes: Cross-Regulated Pathways Playing Major Roles in Hepatic Stellate Cells Activation and Liver Fibrosis

Abstract

Chronic liver injury, regardless of the underlying disease, results in gradual alteration of the physiological hepatic architecture and in excessive production of extracellular matrix, eventually leading to cirrhosis Liver cellular architecture consists of different cell populations, among which hepatic stellate cells (HSCs) have been found to play a major role in the fibrotic process. Under normal conditions, HSCs serve as the main storage site for vitamin A, however, pathological stimuli lead to their transdifferentiation into myofibroblast cells, with autophagy being the key regulator of their activation, through lipophagy of their lipid droplets. Nevertheless, the role of autophagy in liver fibrosis is multifaceted, as increased autophagic levels have been associated with alleviation of the fibrotic process. In addition, it has been found that HSCs receive paracrine stimuli from neighboring cells, such as injured hepatocytes, Kupffer cells, sinusoidal endothelial cells, which promote liver fibrosis. These stimuli have been found to be transmitted via exosomes, which are incorporated by HSCs and can either be degraded through lysosomes or be secreted back into the extracellular space via fusion with the plasma membrane. Furthermore, it has been demonstrated that autophagy and exosomes may be concomitantly or reciprocally regulated, depending on the cellular conditions. Given that increased levels of autophagy are required to activate HSCs, it is important to investigate whether autophagy levels decrease at later stages of hepatic stellate cell activation, leading to increased release of exosomes and further propagation of hepatic fibrosis.

Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy

“…Free fatty acids released by LD degradation are thought to be the energy sources for the fibrogenic response in HSCs. Blocking autophagy promoted lipid accumulation in HSCs with a quiescent phenotype, and attenuated liver fibrosis in vivo [ 41 ]. At present, no study has confirmed that huc-MSC-derived exosomes promote the deactivation of fibrogenic HSCs, which is related to autophagic regulation, but apparently more LDs accumulated in the cytoplasm of HSC-T6 cells in the HSTP1-Exos treated group.…”

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

“…87 Numerous reports have demonstrated that HSC-derived exosomes actively participate in the pathological changes of various liver diseases, all of which are achieved by changes in the protein levels of key signaling pathway molecules. [88][89][90][91]…”

Heparanase Expression Propagates Liver Damage in CCL4-Induced Mouse Model

“…Autophagy plays a crucial role in hepatic homeostasis, and its deregulation is associated with liver diseases [25]. Studies have demonstrated that transformation of quiescent HSCs from the adipogenic to the myofibroblast profile, a hallmark in the propagation of hepatic fibrosis, is mediated through stress-induced autophagy [25,26]. We previously reported that heparanase promotes autophagy by suppressing, among other effects, mTORC1 activity [27][28][29].…”