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From lung to gut - the Wnt signaling pathway transforms cell fate
June 03, 2004Researchers 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."
BioMed Central Limited
"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."
BioMed Central Limited
Stem Cells Current Events and Stem Cells News RSSNew discovery about the formation of new brain cells
The generation of new nerve cells in the brain is regulated by a peptide known as C3a, which directly affects the stem cells' maturation into nerve cells and is also important for the migration of new nerve cells through the brain tissue, reveals new research from the Sahlgrenska Academy published in the journal Stem Cells.
Umbilical cord blood stem cell transplant may help lung, heart disorders
Two separate studies published in the current issue of Cell Transplantation (18:8), - now freely available on-line have shown that transplanted human-derived umbilical cord blood (UCB) stem cells transplanted in an animal model had positive therapeutic effects on specific lung and heart disorders the animal models.
Gene mismatch influences success of bone marrow transplants
A commonly inherited gene deletion can increase the likelihood of immune complications following bone marrow transplantation, an international team of researchers reports in the November 22 advance online issue of Nature Genetics.
New research shows versatility of amniotic fluid stem cells
For the first time, scientists have demonstrated that stem cells found in amniotic fluid meet an important test of potential to become specialized cell types, which suggests they may be useful for treating a wider array of diseases and conditions than scientists originally thought.
First reconstitution of an epidermis from human embryonic stem cells
Stem cell research is making great strides. This is yet again illustrated by a study carried out by the I-STEM* Institute (I-STEM/ Inserm UEVE U861/AFM), published in the Lancet on 21 November 2009. The I-STEM team, directed by Marc Peschanski has just succeeded in recreating a whole epidermis from human embryonic stem cells.
Bone Implant Offers Hope for Skull Deformities
A synthetic bone matrix offers hope for babies born with craniosynostosis, a condition that causes the plates in the skull to fuse too soon.
Your Own Stem Cells Can Treat Heart Disease
The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells.
Is hepatic differentiation of embryonic stem cells induced by valproic acid and cytokines?
Embryonic stem (ES) cells, known for their capacity to proliferate indefinitely and differentiate into almost all types of cells including hepatocytes, have raised the hope of cellular replacement therapy for liver failure.
Paradoxical protein might prevent cancer
One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.
U of M researchers find 2 units of umbilical cord blood reduce risk of leukemia recurrence
A new study from the Masonic Cancer Center, University of Minnesota shows that patients who have acute leukemia and are transplanted with two units of umbilical cord blood (UCB) have significantly reduced risk of the disease returning.
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