Modeling fatty liver disease and progression with stem cell derived hepatocytes

TL;DR

This paper describes a new model using stem cell-derived liver cells to study fatty liver disease progression and how it leads to inflammation and liver damage.

Contribution

The novel contribution is the development of a MASLD model using hiPSC-derived hepatocytes that captures disease progression and paracrine signaling effects.

Findings

Hepatocyte-like cells derived from hiPSCs showed steatotic phenotypes when exposed to free fatty acids.

Biochemical cues from these cells activated fibroblasts, increasing inflammation and ECM deposition.

The model demonstrates how hepatocyte-stroma interactions drive MASH and fibrosis progression.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most pervasive liver disorders. It can progress to metabolic dysfunction-associated steatohepatitis (MASH), hallmarked by increased inflammation and inclination to permanent liver damage. Given the limited treatment options available to patients, models that recapitulate critical features of disease pathogenesis are needed to improve drug development. Here, a MASLD model was developed by differentiating hepatocyte-like cells (HLCs) from human induced pluripotent stem cells (hiPSCs) in 2D and 3D, in which hepatic aggregates exhibited enhanced functionality. Induced HLCs exposed to free fatty acids led to a steatotic phenotype, partially reducing hepatic function. Biochemical cues released from induced HLCs promoted activation of fibroblasts, resulting in increased inflammatory cytokine secretion and extracellular matrix (ECM) deposition. These findings suggest paracrine signaling from hepatocytes to the surrounding stroma can trigger the progression of MASH and fibrosis. Collectively, our results demonstrate the utility of hiPSC derivatives for modeling liver diseases and reveal how heterotypic interactions can drive disease progression.

The online version contains supplementary material available at 10.1038/s41598-025-34762-1.

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