# Modeling hepatic fibrosis in TP53 knockout iPSC‐derived human liver organoids

## TL;DR

Researchers created a human liver organoid model with a TP53 gene knockout to study liver fibrosis, showing fibrotic features and early cancer markers, which could help in developing new treatments.

## Contribution

A novel TP53 knockout iPSC-derived organoid model that recapitulates early liver fibrosis and cancer features.

## Key findings

- TP53KO-eHEPOs showed increased expression of fibrosis markers like PDGFRB and COL1A1.
- Histological analysis confirmed advanced fibrotic hallmarks in the organoids.
- Exposure to profibrotic medium enhanced fibrotic phenotypes in the model.

## Abstract

Hepatic fibrogenesis is characterized by the excessive accumulation of extracellular matrix proteins, ultimately predisposing to hepatocarcinogenesis. The lack of reliable models that faithfully recapitulate early stage fibrogenesis is one of the main limitations in identifying translationally relevant therapeutics. Here, we establish a model using CRISPR/Cas9‐mediated TP53 knockout iPSC (endoderm)‐derived human hepatic organoids (eHEPOs) to mimic human liver fibrosis. Transcriptomic profiling of TP53KO‐eHEPOs revealed enrichment of pathways associated with inflammation, ECM remodeling, and fibrosis, with notable alterations in pivotal fibrotic regulators. We also find increased expression of myofibroblasts and fibrosis markers (PDGFRB, COL1A1, COL3A1, COL11A1) and early liver cancer markers (GPC3 and MUC1). Histological analysis confirmed advanced fibrotic hallmarks and exposure to an exogenous profibrotic environment (pf‐ME) further enhanced these fibrotic phenotypes. This model provides a valuable platform for exploring the role of key driver genes, such as TP53, in the initiation and progression of fibrosis, enabling the study of hepatic progenitor cell transformation across diverse microenvironmental contexts. As such, it holds the potential for advancing early stage drug discovery and the identification of novel therapeutic targets for the treatment of liver fibrosis.

This study developed iPSC‐derived human liver organoids with TP53 gene knockout to model human liver fibrosis. These organoids showed elevated myofibroblast activation, early disease markers, and advanced fibrotic hallmarks. The use of profibrotic differentiation medium further amplified the fibrotic signature seen in the organoids. Therefore, this model offers a promising platform for discovering antifibrotic therapies.