# Oxidative stress and GPX2 control pancreatic vs. non-pancreatic cell fate in human endoderm

## TL;DR

This study shows that oxidative stress and the enzyme GPX2 determine whether human stem cells become pancreatic or liver cells, which could help in developing cell therapies for diabetes and liver diseases.

## Contribution

The study identifies GPX2 and oxidative stress as key regulators of pancreatic versus non-pancreatic cell fate in human endoderm differentiation.

## Key findings

- GPX2 deficiency leads to hepatic-like progenitor differentiation under pancreas-promoting conditions.
- Oxidative stress acts as a gatekeeper of pancreatic fate by regulating lineage commitment through transcription factors.
- Manipulating oxidative stress can recapitulate or rescue the effects of GPX2 loss.

## Abstract

Cell fate decisions in human endoderm development are tightly regulated, yet the role of metabolic products remains elusive. The endodermal posterior foregut gives rise to pancreas, liver, and intestine. Here, we identify Glutathione Peroxidase 2 as a critical regulator of human posterior foregut differentiation, revealing oxidative stress as a key determinant of pancreatic versus non-pancreatic cell fate. Cells lacking Glutathione Peroxidase 2 under pancreas-promoting conditions differentiate also into hepatic-like progenitors. Through bulk and single-cell transcriptomics, chromatin accessibility profiling, and functional studies, we reveal that Glutathione Peroxidase 2 orchestrates lineage commitment by regulating key transcription factors, leading to emergence of multilineage liver and intestinal progenitors. Mechanistically, Glutathione Peroxidase 2 deficiency triggers extracellular matrix remodeling, activating bone morphogenetic protein signaling and skewing differentiation from the pancreatic lineage. Manipulating oxidative stress recapitulates or rescues Glutathione Peroxidase 2 loss effects, establishing oxidative stress as a gatekeeper of pancreatic fate. Controlling oxidative stress during in vitro differentiation could advance regenerative medicine applications.

The role of metabolic processes in endoderm differentiation remains elusive. Here, the authors discover that oxidative stress and GPX2 determine whether human stem cells differentiate into pancreatic or liver tissue. This finding could improve cell-based therapies for diabetes and liver diseases.