Comprehensive review of the vascular niche in regulating liver regeneration, fibrosis, and hepatocellular carcinoma

The liver serves as a crucial regulatory center in the human body, orchestrating various essential physiological processes and maintaining homeostasis. This organ is heterogeneous, consisting of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells. These cells are intricately linked in structure and communicate via autocrine and paracrine signaling, playing key roles in the regulation of liver regeneration and fibrosis following injury. In this review, we provide a brief overview of the different cell types within the vascular niche. Moreover, we discuss some of the molecular mechanisms within this niche that guide liver regeneration and fibrosis, as well as hepatocellular carcinoma. It is important to highlight that developing new treatments for liver diseases necessitates a comprehensive understanding of these cellular and molecular mechanisms. After damage, the liver's repair process is initiated, and vascular endothelial cells, liver stellate cells, and macrophages are reprogrammed to regulate the dynamic balance between regeneration and fibrosis through interactions of various cytokines. Prolonged stimulation of a fibrotic liver leads to hepatocellular carcinoma, an irreversible process. Upon acute liver injury, liver sinusoidal endothelial cells (LSECs) secrete hepatocyte growth factor (HGF) and WNT2 to stimulate hepatocyte proliferation. Notably, elevated HIF2α expression in LSEC nuclei promotes membrane localization of endothelial protein C receptor (EPCR), which recruits circulating platelets to collaboratively establish a pro-regenerative “niche” facilitating hepatocyte replication. With persistent injury, vascular endothelial cells undergo phenotypic reprogramming characterized by enhanced secretion of pro-inflammatory mediators including IGFBP7, ADAMTS1, CTGF, and VCAM. These molecular signals orchestrate inflammatory cell infiltration, activate hepatic stellate cells, and drive excessive extracellular matrix deposition, ultimately leading to hepatocyte functional impairment. The hypoxic microenvironment in hepatocellular carcinoma drives endothelial production of pro-angiogenic factors, including diacylglycerol kinase gamma (DGKG) and angiopoietin-2 (ANGPT2), which activate vascular endothelial cell proliferation and migration, fueling tumor angiogenesis. This pathological neovascularization facilitates tumor expansion and metastatic progression.