Sinusoidal Endothelial Cell Function in Liver Diseases

Liver sinusoidal endothelial cells (LSECs) form a specialised, fenestrated barrier between the bloodstream and hepatocytes, uniquely adapted to regulate nutrient exchange, clearance of macromolecules and immune surveillance. Under homeostatic conditions, LSECs maintain hepatic stellate cell and Kupffer cell quiescence through the release of vasodilators such as nitric oxide and a repertoire of angiocrine signals that support tissue repair. In response to acute injury, they orchestrate regeneration by sensing changes in blood flow and releasing growth factors that drive hepatocyte proliferation. However, chronic insults—including metabolic stress, viral infection or toxic injury—induce LSEC capillarisation, characterised by loss of fenestrae, basement membrane deposition and diminished endocytic capacity. This phenotypic shift increases vascular resistance, promotes stellate cell activation and initiates fibrogenesis. Moreover, dysfunctional LSECs contribute to a proinflammatory microenvironment and facilitate tumour cell adhesion, thus linking vascular remodelling to the progression of fibrosis, cirrhosis and carcinoma. Restoring or preserving LSEC phenotype has therefore emerged as a promising therapeutic avenue to prevent disease advancement and to enhance regenerative outcomes.

Research from Nature Portfolio

Recent studies have identified myeloid-derived growth factor (MYDGF) as a mechanically induced angiocrine signal released by hepatic endothelium following partial hepatectomy. MYDGF activates MAPK and STAT3 pathways in primary human hepatocytes and three-dimensional organoids, enhancing proliferation and survival, while its deletion in mice impairs regeneration and its gene delivery accelerates liver regrowth.

Foundational work has elucidated how the endothelial transcription factor ERG dynamically regulates TGFβ-SMAD signalling to protect against fibrogenesis. ERG promotes SMAD1-driven homeostatic responses and restricts SMAD3 activity, thereby preventing endothelial-to-mesenchymal transition. Loss of ERG in endothelial cells triggers spontaneous liver fibrosis and sensitises to injury-induced scarring, establishing ERG as a key gatekeeper of vascular health.

Sinusoidal Endothelial Cell Function in Liver Diseases publication trend

The graph below shows the total number of articles in sinusoidal endothelial cell function in liver diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Liver sinusoidal endothelial cells (LSECs): Highly specialised endothelial cells lining liver sinusoids, responsible for selective filtering, scavenging and signalling functions.

Fenestrae: Transcellular pores in LSECs that permit efficient exchange of fluids, solutes and lipoproteins between blood and hepatocytes.

Capillarisation: Phenotypic transformation of LSECs involving loss of fenestrae, formation of a continuous basement membrane and reduced permeability.

Angiocrine signal: Growth or survival factor secreted by endothelial cells that modulates parenchymal cell behaviour and tissue regeneration.

Fibrogenesis: The process by which excessive extracellular matrix proteins accumulate in the liver, leading to fibrosis and compromised organ function.

Partial hepatectomy (PHx): Surgical removal of a portion of the liver used experimentally to study regenerative mechanisms.

References

1. Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes. Nature Communications (2024).
2. Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis. Nature Communications (2017).
3. Oit3, a promising hallmark gene for targeting liver sinusoidal endothelial cells. Signal Transduction and Targeted Therapy (2023).
4. Endothelial TAZ inhibits capillarization of liver sinusoidal endothelium and damage-induced liver fibrosis via nitric oxide production. Theranostics (2023).
5. The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver. Frontiers in Physiology (2020).