From lung to gut – the Wnt signaling pathway transforms cell fate

Researchers have uncovered a cellular mechanism that can alter the fate of progenitor cells that normally generate the lung, causing them to create gut cells instead. The findings, which are published this week in the top-tier Open Access journal, Journal of Biology, could help researchers hoping to use adult stem cells for therapeutic purposes.

Brigid Hogan and Tadashi Okubo, from Duke University Medical Center, studied the lungs of transgenic mice that had developed under the influence of artificially high levels of activity in the Wnt signaling pathway, caused by the presence of an activated beta catenin gene. They found that although externally the lungs looked normal, the interior of the lungs had lost the normal branching tree-like structure lined with rounded alveolar cells. Instead, a few wide bronchial tubes opened directly into large sacs that were lined with a rapidly proliferating cuboidal epithelium.

Looking more closely at these epithelial cells, the researchers found that many of them were not expressing genes typical of lung cells, such as the genes encoding secretoglobin and surfactants. In addition, microarrays comparing the transgenic cells with normal lung epithelial cells showed a general reduction in the expression of lung-specific genes and a strong expression, instead, of genes characteristic of intestinal cells.

“A striking feature of the microarray data was the high expression in transgenic lungs of genes normally associated with the specification and differentiation of gut secretory cell lineages,” say Hogan and Okubo. These included the gene encoding the Atoh1 transcription factor, which is normally turned off in lung cells.

“In particular there was a very high level of expression of genes characteristic of Paneth cells, which are normally found in the base of crypts in the small intestine,” they continue.

Signaling downstream of beta catenin normally occurs in cells that have been activated by molecules of the Wnt family. Wnts are known to play a role in the development of the gut, and their presence in developing lungs suggests that they also function in lung development. Wnts also control cell fate in cells of the epidermis and hair follicle.

“These results show that hyperactive Wnt signaling in lung progenitor cells can induce a dramatic shift in lineage commitment and the generation of intestinal cell types,” write the authors. Understanding the mechanism by which these progenitor cells can switch their fate and create other tissues of the same embryonic origin could be of great importance to researchers working with adult stem cells, who would like to program cells to adopt particular fates.

The research could also shed light on a condition known as Barrett’s esophagus, where patches of the esophagus lining alter to resemble the lining of the intestine – a process known as intestinal metaplasia. Hogan and Okubo believe that there is a possibility that “elevated Wnt signaling in adult stem cells or progenitor cells is at least one factor promoting intestinal metaplasia in humans.”

This press release is based on the following article:

Hyperactive Wnt signaling changes developmental potential of embryonic lung endoderm
T Okubo and BLM Hogan
Journal of Biology 2004, 3:11
To be published 8 June 2004

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