Hepatic Stellate Cell Dynamics in Liver Pathologies

Hepatic stellate cells (HSCs) are pericyte-like cells residing in the space of Disse that play a pivotal role in both homeostatic and pathological processes of the liver. In healthy tissue they store vitamin A in lipid droplets and maintain extracellular matrix (ECM) turnover. Upon acute or chronic liver injury, HSCs undergo activation, a process of trans-differentiation into myofibroblast-like cells characterised by loss of retinoid stores, expression of α-smooth muscle actin and prolific secretion of ECM components such as collagen I. This fibrogenic conversion is driven by inflammatory mediators, transforming growth factor-β1 signalling and metabolic reprogramming, and underlies the progression from fibrosis to cirrhosis. Activated HSCs also interact bidirectionally with immune cells, hepatocytes and endothelial cells, influencing tissue repair, angiogenesis and tumour microenvironment modulation. The dynamic plasticity of HSCs holds global significance: their reversibility in early stages presents opportunities for anti-fibrotic therapy, while their persistent activation contributes to liver failure and predisposes to hepatocellular carcinoma. Emerging research focuses on elucidating the molecular checkpoints of activation, metabolic dependencies and intercellular crosstalk, with a view to designing targeted interventions that can halt or reverse fibrogenesis.

Research from Nature Portfolio

Recent studies have shown that naturally occurring flavonoids can modulate HSC activation. One investigation demonstrated that quercetin, administered in experimental models of biliary obstruction and chemical injury, attenuates fibrotic deposition by suppressing the TGF-β1/Smad axis and by inhibiting autophagy through the PI3K/Akt pathway. This dual modulation reduced ECM accumulation and limited the transition of HSCs into proliferative myofibroblasts. In parallel, advanced three-dimensional tumour spheroid models have highlighted the role of activated HSCs in promoting chemoresistance and invasive behaviours in hepatocellular carcinoma. These spheroid studies revealed that HSC-derived collagen I and matrix metalloproteinase 9 enhance cell-cell adhesion and extracellular remodelling, thereby diminishing drug penetration and fostering tumour cell migration. Furthermore, characterisation of reciprocal signalling loops involving TGF-β1 and CD147 has uncovered a positive feedback circuit that perpetuates HSC activation. Disruption of this loop, via combined inhibition of TGF-β receptors and blockade of CD147, was sufficient to reverse fibrogenic phenotypes in vitro, suggesting novel combinatorial strategies for antifibrotic therapy.

Hepatic Stellate Cell Dynamics in Liver Pathologies publication trend

The graph below shows the total number of articles in hepatic stellate cell dynamics in liver pathologies across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatic stellate cell: Perisinusoidal liver cell that stores vitamin A and, upon activation, becomes a myofibroblast-like producer of extracellular matrix.

Activation: Phenotypic conversion of quiescent HSCs into proliferative, contractile and ECM-secreting myofibroblasts.

Trans-differentiation: Cellular process by which one mature somatic cell transforms into another cell type without reverting to a pluripotent state.

Fibrogenesis: Sequential events leading to excessive deposition of ECM components, resulting in scar formation and impaired organ function.

Extracellular matrix: Complex network of proteins and glycoproteins, including collagens and fibronectin, that provides structural and biochemical support to cells.

References

1. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells (2020).
2. Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-β1/Smads and PI3K/Akt pathways. Scientific Reports (2017).
3. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells (2019).
4. Hepatic Stellate Cells and Hepatocarcinogenesis. Frontiers in Cell and Developmental Biology (2020).
5. Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids. Scientific Reports (2016).
6. Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Scientific Reports (2015).