It’s easy to think of the esophagus as a simple food pipe connecting the mouth and the stomach, but architecturally, it’s far more complex. Unlike other parts of the gastrointestinal tract, it has a keratinised lining and a distinctive combination of smooth and striated muscle, making it uniquely equipped for its job.
Despite its importance, much about esophageal development remains poorly understood, especially the role of Lgr5-positive stem cells. These cells are known to be involved in conditions such as esophageal cancer, but their contributions to organ growth and function are still unclear.
“Uncovering this innate complexity helps us better understand how the organ develops and functions under normal conditions and provides the foundation for studying how diseases such as cancer arise and progress in the esophagus,” said Nick Barker, Research Director at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB).
Teaming up with researchers at Nanyang Technological University, Singapore, Barker’s team set out to investigate the existence and function of Lgr5+ cells during esophageal development. By performing single-cell RNA sequencing (scRNA-seq) at various stages—embryonic, neonatal and adult—they were the first to identify Lgr5+ cells in both the epithelial and muscle layers of the esophagus.
Advanced mouse models allowed the researchers to track Lgr5+ cells in real time, following the stem cells’ contributions to tissue development over months. Combining scRNA-seq with spatial transcriptomics, Barker and colleagues uncovered dynamic populations of Lgr5+ cells, their distinct expression profiles, and their distribution across the esophagus. They also identified a unique pool of Lgr5+ cells with stem cell-like properties, capable of long-term retention in both epithelial and muscle layers.
“It was remarkable to observe for the first time that the fast-cycling esophageal epithelium contains a population of cells that are retained over time,” said Barker. These cells were also found to play a pivotal role in the growth and maturation of the epithelial layer, added Barker.
The team discovered that Lgr5+ cells act as a source of Wnt6, a signalling molecule essential for epithelial growth. Using organoid systems—miniature versions of the esophagus grown in a lab—they showed that removing Lgr5+ cells reduced Wnt6 levels and impaired organoid growth, thus supporting their original hypothesis.
Looking ahead, Barker’s team is exploring how Lgr5+ cells contribute to esophageal cancers, with hopes of developing targeted treatments to improve outcomes.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB), A*STAR Singapore Immunology Network (A*STAR SIgN) and A*STAR Infectious Diseases Labs (A*STAR IDL).
