SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis

Abstract

Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.

Multifunctional YY1 in Liver Diseases

“…29,30 Hepatic fibrosis is a chronic condition that initiates a cascade of biochemical and biophysical changes in the liver microenvironment, causing necrosis and apoptosis of hepatocytes (highly specialized epithelial cells) and liver sinusoidal endothelial cells (LSECs) through the release of inflammatory mediators and profibrotic cytokines and activation of hepatic stellate cells (HSCs). 31 Collagen I and collagen XVIII are the principal types of collagen deposited in hepatic fibrosis and cirrhosis, and studies have indicated that YY1 can regulate the transcription of the genes encoding these two important factors.…”

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

“…In contrast, in chronic liver diseases an imbalance of pro-fibrogenic and antifibrogenic mechanisms causes persistent activation of proliferating, contractile, and migrating myofibroblasts that lead to excessive production of ECM [8,9]. The liver's fate to either pass into an anti-fibrotic scar-dissolving stage or to proceed into an uninhibited fibrosis-promoting stage is hereby mainly regulated by non-parenchymal cells (NPCs), including Kupffer cells and other immune cells [10][11][12]. Thus, hepatocyte apoptosis and release of damage-associated patterns (DAMPs) by hepatocytes not only activate HSCs directly but also induce recruitment and activation of lymphocytes and macrophages that contribute to promotion of HSC trans-differentiation and myofibroblast activation by producing pro-inflammatory and pro-fibrogenic cytokines [13,14].…”

Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis

“…This also results in liver sinusoidal endothelial cell (LSEC) capillarization and poor extravasation to liver fibrogenic cells. 2 MicroRNAs (miRNAs) play an important role in a myriad of liver diseases, ranging from metabolic diseases, alcoholic fatty liver disease (AFLD), viral hepatitis, and HCC. The family of miR-29 has four members: miR-29a, miR-29b1, miR-29b2, and miR-29c, with identical seed sequences.…”