Can you write reference papers ( highly cited, high impact journals from last 5 years) supporting the points mentioned in the review article points written here in the text LSECs' Influence on Hepatic Stellate Cell Activation and Collagen Deposition Leading to Fibrosis
LSECs play a critical role in the regulation of hepatic stellate cells (HSCs), which are the primary cells responsible for collagen deposition and fibrosis in the liver. Under healthy conditions, LSECs help maintain HSCs in a quiescent, non-fibro genic state by producing soluble factors such as nitric oxide (NO). NO helps to keep HSCs inactive and prevents the excessive production of extracellular matrix (ECM) proteins, including collagen. However, in the context of chronic liver injury (due to viral hepatitis, alcohol abuse, or metabolic disorders like non-alcoholic fatty liver disease), LSECs undergo functional changes that lead to the activation of HSCs.
When LSECs become dysfunctional, they lose their ability to produce sufficient NO and other anti-fibrotic signals. As a result, HSCs are activated, transforming into myofibroblasts—cells that are responsible for secreting large amounts of collagen and other ECM proteins. This excessive collagen deposition leads to the disruption of the liver's normal architecture, causing scarring, and contributing to the progression of fibrosis. Additionally, capillarization of LSECs (where they lose their fenestrations) further exacerbates fibrosis by restricting nutrient and oxygen supply to hepatocytes, thereby promoting liver damage and inflammation.
Signaling Pathways Involved in LSEC-Mediated Fibrosis and Endothelial Dysfunction
Several signaling pathways are involved in LSEC-mediated fibrosis and endothelial dysfunction. One key pathway is the transforming growth factor-beta (TGF-β) signaling pathway. TGF-β is a potent pro-fibrotic cytokine that plays a major role in the activation of HSCs. Dysfunctional LSECs can produce increased levels of TGF-β, which directly stimulates HSC activation and collagen production. Moreover, LSECs themselves become more susceptible to the effects of TGF-β, which contributes to their capillarization and loss of normal function.
Another important pathway is the vascular endothelial growth factor (VEGF) signaling pathway. Under normal conditions, VEGF maintains the fenestrated structure of LSECs and supports their survival. In chronic liver disease, reduced VEGF signaling leads to the capillarization of LSECs, contributing to fibrosis. Capillarized LSECs exhibit characteristics similar to vascular endothelial cells, further promoting inflammation and fibrosis by interacting with immune cells and HSCs in a pathological manner.
Oxidative stress is also a significant factor in LSEC-mediated fibrosis. In conditions such as alcoholic liver disease or fatty liver disease, increased oxidative stress leads to the production of reactive oxygen species (ROS), which damage LSECs and contribute to their dysfunction. This, in turn, leads to the activation of pro-fibrotic signaling pathways such as platelet-derived growth factor (PDGF), which further stimulates HSC activation and collagen production.
Changes in LSEC Phenotype Exacerbate Fibrosis and Liver Scarring
Recent studies have shown that changes in LSEC phenotype, such as capillarization and loss of anti-fibrotic signaling, significantly exacerbate fibrosis and liver scarring. In a study by Li et al. (2024), it was demonstrated that LSECs from fibrotic livers exhibited increased expression of TGF-β and decreased expression of NO-producing enzymes. These changes were correlated with heightened HSC activation and collagen deposition, indicating a direct role of LSEC dysfunction in fibrosis progression. The study also highlighted that restoring NO levels in LSECs helped mitigate fibrosis by inhibiting HSC activation.
Similarly, research by Yokoyama et al. (2024) emphasized that capillarized LSECs were less effective at filtering blood and regulating immune cell recruitment. The loss of fenestrations in LSECs led to the enhanced recruitment of inflammatory macrophages, which further stimulated HSC activation and promoted liver scarring. Targeting LSEC capillarization was proposed as a potential therapeutic strategy to prevent fibrosis.
These findings underscore the critical role of LSECs in the progression of liver fibrosis and suggest that therapeutic approaches aimed at restoring LSEC function could be effective in reducing fibrosis and preventing liver disease progression.