Hepatic Stellate Cell Biology and Liver Fibrosis Mechanisms

Hepatic stellate cells (HSCs) are perisinusoidal, vitamin A–storing cells that reside in the space of Disse and contribute to liver homeostasis, regeneration and immunoregulation. In their quiescent state, HSCs maintain extracellular matrix (ECM) composition and support sinusoidal endothelial fenestration. Following chronic liver injury or metabolic stress, HSCs undergo activation, adopting a myofibroblast‐like phenotype characterised by proliferative capacity, contractility and enhanced synthesis of fibrillar collagens and other ECM components. This persistent ECM deposition leads to increased tissue stiffness, capillarisation of sinusoids and impaired hepatic microcirculation, culminating in fibrosis and, ultimately, cirrhosis. Activation is orchestrated by cytokines such as transforming growth factor-β, platelet-derived growth factor and hedgehog ligands released by injured hepatocytes, Kupffer cells and endothelial cells. Cross-talk among these cell types exacerbates fibrogenesis and promotes a profibrotic milieu. Progressive matrix remodelling also influences mechanotransduction pathways, reinforcing HSC activation in a feed-forward loop. Emerging evidence emphasises the heterogeneity of HSC subpopulations, the roles of senescence and autophagy in fibrogenic resolution, and the impact of ageing on mechanosensing and growth factor release. Understanding these interdependent mechanisms underpins the development of anti‐fibrotic therapies and informs strategies for cell-based liver repair.

Research from Nature Portfolio

Human induced pluripotent stem cell–derived co-culture models have demonstrated that genetic modulation of hepatic stellate–like cells can enhance hepatocytic maturation. Overexpression of LIM homeobox 2 in stellate-like cells promotes extracellular matrix remodelling through increased laminin and collagen deposition, fostering improved albumin expression and metabolic function in adjacent hepatocyte progenitors. This work highlights the utility of genetically engineered stellate cells for studying stromal–parenchymal interactions and suggests potential avenues for improving in vitro liver platforms used in drug screening and disease modelling.

Hepatic Stellate Cell Biology and Liver Fibrosis Mechanisms publication trend

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

Technical terms

Hepatic stellate cell: A liver-resident perisinusoidal cell that stores vitamin A and, upon activation, transdifferentiates into a fibrogenic myofibroblast.

Extracellular matrix (ECM): A complex network of collagens, glycoproteins and proteoglycans that provides structural support and regulates cell behaviour.

Quiescence: A reversible, non-proliferative state in which HSCs maintain normal liver architecture and ECM balance.

Activation: The process by which quiescent HSCs become proliferative, contractile and ECM-producing myofibroblasts in response to liver injury.

Myofibroblast: A contractile, collagen-secreting cell phenotype derived from activated HSCs that drives fibrosis.

Mechanotransduction: Cellular sensing and conversion of mechanical stimuli, such as matrix stiffness or shear stress, into biochemical signals.

References

1. Secretome of senescent hepatic stellate cells favors malignant transformation from nonalcoholic steatohepatitis-fibrotic progression to hepatocellular carcinoma. Theranostics (2023).
2. Human iPSC-derived liver co-culture spheroids to model liver fibrosis. Biofabrication (2024).
3. Impaired integrin α5/β1‐mediated hepatocyte growth factor release by stellate cells of the aged liver. Aging Cell (2020).
4. LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. Scientific Reports (2019).