Metaplasia is defined as the replacement of a completely differentiated cell type by another. There are several classic examples of metaplasia, one of the most common is called Barrett’s esophagus. Barrett’s esophagus is characterized by the replacement of keratinocytes by columnar cells in the lower esophagus after chronic acid reflux. This metaplasia is considered a precancerous lesion that increases the risk of this esophageal adenocarcinoma by about 50 times. Nevertheless, the mechanisms involved in the development of esophageal metaplasia are still partially unknown.
In a new study published in Stem cells cells, researchers led by Mr. Benjamin Beck (FNRS research associate and WELBIO researcher at IRIBHM, Université libre de Bruxelles, Belgium), report on the mechanisms involved in the transdifferentiation of esophageal keratinocytes into columnar cells.
Alizée Vercauteren Drubbel and colleagues used state-of-the-art genetic tools and mouse models to dissect the molecular mechanisms by which esophageal cells can participate in metaplasia. In cooperation with prof. Sachiyo Nomura (Tokyo Medical University, Japan), showed that Hedgehog pathway reactivation occurs in epithelial cells after chronic acid reflux. The only reactivation this time in normal esophageal cells changes them and makes them look like embryonic esophageal cells. After that, the subset of these cells turns into columnar cells.
It was really surprising to see how cells from the esophagus slowly change over time and gain the characteristics of other tissues just by activating the signaling pathway in vivo. “
Alizée Vercauteren Drubbel, the first author of the study
The authors show that the hedgehog pathway alters the squamous differentiation program in almost all esophageal cells, but induces complete flat conversion into a column only into a subset of progenitors. Interestingly, an embryonic-like epigenetic and transcriptomic program precedes the column conversion, suggesting that keratinocytes should be dedifferentiated before activating another differentiation program. Conditional knockout in vivo shows that the transcription factor Sox9 plays a key role in the column conversion process.
In conclusion, this paper highlights the mechanisms that modulate cellular plasticity that may represent the first step in transdifferentiation and development of esophageal metaplasia. The incidence of esophageal adenocarcinoma has increased dramatically over the past decades. This increase appears to be the result of an increased prevalence of Barrett’s esophagus. Therefore, “we hope that a better understanding of the processes involved in the development of metaplasia and their progression to cancer will help identify people at high risk of developing cancer.” commented Benjamin Beck, the last and appropriate author of this study.
Free University of Brussels
Drubbel, AV, and others. (2021) Hedgehog reactivation in esophageal progenitors involves an embryo-like program to initiate colonic metaplasia. Stem cells cells. doi.org/10.1016/j.stem.2021.03.019.