Reconciling the new with the old

There is constant turnover in cells lining the gut.  In fact, this happens as often as once a day by dividing stem cells that live in the mouth, esophagus, and intestines.  The nature of stem cells in the esophagus has become a matter of debate, and it’s an important one to resolve if we’re going to understand diseases that affect cell turnover, like esophageal cancer, which has increased 3-8 fold in just the past 40 years.

Studies on cell turnover in the gut date back to the 1960s, when researchers injected radioactive thymidine into young mice.  Thymidine, often represented by the letter “T”, is one of the four DNA base pairs.  As cells divide, they incorporate radioactive thymidine into their DNA, which lets researchers track the cells over time.  Using this technique, all cells appear to divide and mature at the same rate in the esophagus.

The funny thing is that more recent discoveries don’t match up with the original reports from the 1960s.  Over the past five years, people have reported small reservoirs of slowly dividing stem cells in the esophagus.  The original “all cells are equal” conclusion is tough to draw from radioisotope labeling, so it’s not surprising that it’s been brought into question.

Science marches on, and now we have much better technology to track cell fate than radioisotopes:  we have transgenic mice.  A paper from the lab of Philip Jones at the Hutchinson-MRC Research Centre in Cambridge capitalized on this technology to sort out stem cells in the esophagus. Their work was published online by the journal Science on July 19, 2012.

The Jones group used two different mouse models to resolve the nature of esophageal stem cells.  The first mouse can turn on green fluorescent protein in the nucleus of all its cells.  Flip a biologic switch by injecting a chemical, and all the cells turn green.  That green signal gets diluted out as cells divide and are sloughed off.  In fact, it’s gone after just a month.  So it appears that there are no slowly dividing cells.  This agrees with the 1960s report.

Their second trick was to use a mouse that can turn on yellow fluorescent protein in cells of the gut.  It works like the first, inject two chemicals and cells turn yellow.  However, this mouse is different in two important ways: only some cells turn yellow, and their offspring stay yellow.  So researchers could track the fate of yellow cells in the esophagus.  Did they all mature and get sloughed off, or did some stick around as a reservoir of future esophagus-lining cells.

Turns out, there is a population of stem cells that sticks around in the esophagus. They divide to maintain their numbers while sending an equal number of daughter cells off to replenish the esophageal lining.  When nothing’s wrong, they divide about twice a week.  In the face of injury, the esophagus is like a boxer, light on its feet.  The stem cells ramp up their number of daughter cells to fix the damage, then settle down and go back to maintaining the status quo.

These nimble cells set the esophagus apart from the rest of the gut, which probably contributes to some of the recent controversy.  Elsewhere, you’ll find small pockets of slowly dividing stem cells. Esophageal cancer and gastric reflux both affect the rate of cell division in the esophagus.  It’s important to know who’s calling the shots on cell turnover when trying to treat these diseases, otherwise we might miss out on finding new treatments.

The original paper:

A Single Progenitor Population Switches Behavior to Maintain and Repair Esophageal Epithelium, Science DOI: 10.1126/science.1218835Published online July 19, 2012.