Are There Stem Cells in the Esophagus and Stomach?

Researchers have identified potential stem cells in human esophagus and stomach, as well as those in metaplastic esophagus that could lead to esophageal cancer, according to the April issue of Gastroenterology.

Stem cells have been reported to exist in the basal layer of the human esophagus—their progeny are believed to become differentiated in the parabasal and superficial layers. These cells might be isolated and studied to develop new therapies for disorders such as Barrett’s esophagus—a premalignant condition in which the stratified squamous epithelium is replaced by a columnar metaplasia.

However, studies of stem cells in the gastrointestinal tract have been limited by the constraints of experimental systems—it is not clear which models are most relevant to the human gastrointestinal tract, or how they differ among benign, premalignant, and neoplastic tissues.

Qiuwei Pan et al. investigated the existence of uncommitted, slowly cycling cells in esophageal and stomach tissues of patients, tracking cells labeled by 5-iodo-2′-deoxyuridine (IdU). Cells that retain this label for more than 29 days, called label-retaining cells, are believed to be a population of adult stem cells—long-lived, multi-potent cells responsible for the replacement of differentiated cells after injury or insult.

The authors injected IdU into 4 patients undergoing esophageal resection for adenocarcinoma. Tissues were collected 7, 11, 29, and 67 days later, from areas of squamous esophagus, Barrett’s esophagus, Barrett’s-associated dysplasia, esophageal adenocarcinoma, and normal stomach.

Pan et al. found label-retaining cells in the human esophagus and stomach that had many features of stem cells (long lived, slow cycling, uncommitted, and multi-potent).

In normal squamous esophagus, label-retaining cells were detected mainly in the basal layer, which became the exclusive location by 67 days (see below figure).

The normal squamous esophageal epithelium. The  interpapillary basal layer is red, the papillary basal layer is green, the parabasal layer is orange, and the superficial layer is brown.

The normal squamous esophageal epithelium. The interpapillary basal layer is red, the papillary basal layer is green, the parabasal layer is orange, and the superficial layer is brown.

These cells were epithelial (in that they contained cytokeratin) and resided adjacent to clusters of proliferating cells. The authors also calculated the epithelial turnover time of the healthy esophageal mucosa to be approximately 11 days (twice that of the intestine).

In normal stomach, Pan et al. identified LRCs in only the neck of the gastric unit; these cells were also epithelial yet undifferentiated (see below figure).

Label-retaining cells (red) in the stomach co-localize with cytokeratin (green) at 11 days post-infusion, confirming the epithelial nature of these cells.

Label-retaining cells (red) in the stomach co-localize with cytokeratin (green) at 11 days post-infusion, confirming the epithelial nature of these cells.

Barrett’s esophagus forms glandular structures; cells proliferate in the base and further up in the glands and become differentiated toward the surface before being lost in the lumen.

In patients, Pan et al. found label-retaining cells only at the base of the Barrett’s glands, through 67 days after infusion of the label. These cells were epithelial and located near proliferating cells, and did not appear to be committed to any particular lineage. LGR5 mRNA, a previously identified marker of intestinal stem cells, was also found at the base of the Barrett’s glands.

Pan et al. conclude that they have demonstrated the existence of a population of slowly cycling, uncommitted cells in the normal and metaplastic human upper gastrointestinal tract. Further studies of these could lead to new approaches for regenerative medicine, and aid diagnosis and determination of prognosis for patients with Barrett’s esophagus.

Read the article online.
Pan Q, Nicholson AM, Barr H, et al. Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus. Gastroenterology 2013;144:761–770.

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