February 26, 2009 — Researchers at the University of Pennsylvania School of Medicine, in Philadelphia, have discovered stem cells in the esophagus of mice that are able to grow into tissue-like structures and form parts of an esophagus lining when placed into immune-deficient mice.1

“The immediate implication is that we’ll have a better understanding of the role of these stem cells in normal biology, as well as in regenerative and cancer biology,” stated senior author Anil Rustgi, MD, professor of medicine and genetics and chief of gastroenterology at Penn. “Down the road we will develop a panel of markers that will define these stem cells and use them in replacement therapy for diseases like gastroesophageal reflux disease [GERD] and to understand Barrett’s esophagus, a precursor to esophageal adenocarcinoma, and how to reverse that before it becomes cancer.”

Diseases of the esophagus are very common, both in the United States and worldwide. “Benign forms include GERD, and millions are affected,” Dr. Rustgi noted.

GERD sometimes can lead to esophagitis, an inflammation of the esophagus. “In some of these cases, esophagitis can lead to a swapping of the normal lining of the esophagus with a lining that looks more like the intestinal lining. That’s called Barrett’s esophagus,” he explained. “This can lead to cancer of the esophagus, which is the fastest rising cancer in the United States, increasing by 7 percent to 8 percent a year.”

To understand normal biology and how injured cells may one day be repaired, researchers set out to identify potential stem cells, which have the ability to self-renew, in the esophagus and to characterize them. The first step was to grow mouse esophageal cells they suspected were adult stem cells. The cells formed colonies that self-renewed, then they grew into esophageal lining tissue in a three-dimensional culture apparatus.

“These tissue culture cells formed a mature epithelium sitting on top of the matrix,” said Dr. Rustgi. “The whole construct is a form of tissue engineering.”

The investigators then tested their pieces of esophageal lining in animals. When the tissue-engineered patches were transplanted under the skin of immunodeficient mice, the cells formed epithelial structures.

In addition, green-stained stem cells in a mouse model of esophageal injury, which mimics what happens during acid reflux, migrated to the injured lining cells and co-labeled with the repaired cells. This indicated involvement of the stem cells in tissue repair and regeneration.

The researchers eventually will develop genetically engineered mouse models to be able to track molecular markers of esophageal stem cells found in a microarray study. The group already has developed a library of human esophageal cell lines and is looking for human versions of markers already identified in mice.

“The ultimate goal is to identify esophageal stem cells in a patient, grow the patient’s own stem cells, and inject them locally to replace diseased tissue with normal lining,” said Dr. Rustgi.

The Penn scientists collaborated with researchers from Massachusetts General Hospital, in Boston, and the Wistar Institute in Philadelphia. The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute.

Reference

1. Kalabis, J., Oyama, K., Okawa, T., et al. (2008). A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. Journal of Clinical Investigation, 118 (12): 3860-69.

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