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Adult Stem Cells in the Pancreas: Who’s Your Daddy?

Few areas of medical research are as contentious as the study of stem cells. Most folks are aware of the ethical and political debate surrounding the use of embryonic stem cells, with the promise of medical advances balanced against objections to the use of fetal tissue.

Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical School

Few areas of medical research are as contentious as the study of stem cells. Most folks are aware of the ethical and political debate surrounding the use of embryonic stem cells, with the promise of medical advances balanced against objections to the use of fetal tissue.

In addition to the ethical dispute, there is also significant scientific controversy in this arena. Nowhere is this truer than in the specific area of pancreatic stem cells, which have been touted as a possible cure for type 1 diabetes. In type 1 diabetes (which used to be called juvenile diabetes, in the days before so many kids started developing obesity-related type 2 diabetes), the insulin-producing pancreatic beta cells are destroyed by an autoimmune process, forcing patients to self-administer insulin to survive. A very few patients can receive pancreatic transplants, but there are technical obstacles to transplantation. Even if those hurdles were overcome, there would still be far too few donor organs to fill the needs of the half million or so patients with type 1 diabetes in the U.S. alone. So it’s easy to understand why there’s so much interest in developing a renewable source of beta cells.

The major question in the field is whether the stem cells have to come from embryos, or if the adult pancreas contains cells that can be expanded and induced to differentiate into mature beta cells. The use of adult stem cells would overcome the most significant moral and political obstacles, since adult kidneys, livers and other organs are routinely used for transplantation without moral objection. This would thus allow the field to advance more rapidly.

But the existence of adult stem cells is scientifically controversial. There is, in fact, some compelling evidence for the existence of adult pancreatic stem cells. These cells are thought to reside along the pancreatic ducts, because this is where new islets seem to form during growth, or when the pancreas is damaged. Additionally, cells harvested from the ducts can be induced to differentiate into beta cells in test tubes, and occasional cells can be seen in the ducts that express some molecular markers of beta cells. There is also evidence that stem cells could reside within the islet itself. These sorts of data have been used to bolster the case for adult stem cells, and there are serious efforts being made by a number of academic and industrial labs to purify and positively identify the putative stem cell in the adult pancreas.

To be fair, however, all of this evidence is a bit indirect. No one has ever been able to point to a particular cell in an islet and say, “Aha, that one there is a stem cell”. When ductal cells are induced to differentiate in a dish, there are small numbers of other cells hanging around, any of which could be the true source of the beta cells.

This uncertainty led a group at Harvard Medical School to go back to basics. Rather than ask “which cells are the adult pancreatic stem cell?” they asked whether such cells exist at all. To accomplish this, they took advantage of a variety of new techniques to perform a so-called genetic lineage test. In a lineage test one permanently “tags” cells in a particular place at a particular time. The tag is usually a special protein that glows an unusual color, or some other protein that can be traced. Without going into too many of the technical details, the activity of this tracer protein is controlled by genetic elements that are only turned on in the cell type of interest. For this experiment, the authors used the control elements of the insulin gene, so that the marker would only be expressed in beta cells.

By using this strategy, the Harvard team was able to tag beta cells in adult mice. They then watched what happened over the course of a year, during which time the islets expanded greatly in size. By examining the islets for the marker protein, the team reasoned it could figure out whether new cells that developed over the course of the year came from stem cells. The thinking goes like this: stem cells that don’t express insulin won’t be tagged, and their daughter cells after cell division won’t be tagged either. If stem cells contribute to the pool of islet cells, one would expect to see a dilution of the tagged cells as the untagged daughter cells slowly filled up the growing islet.

This is not what happened. What happened was that the percentage of tagged cells remained the same in the islets over time. The only way this could occur is if the new beta cells that appeared were derived from the old beta cells. In other words, beta cells in aging mice are created from pre-existing beta cells, rather than representing new cells derived of stem cells.
To put it delicately, this result is not exactly what the adult stem cell field was waiting to hear. True, the possibility is left open that stem cells do exist in the adult pancreas, but only in very small numbers that don’t contribute much to the increased mass of beta cells during aging or after pancreatectomy, as the authors concede. Several other groups are now actively trying to replicate the result, and to perform similar lineage tracing experiments to see if tagged ductal cells can end up producing insulin in the islet.
While these studies are being performed, it would seem prudent to pay attention to one of the key implications of this study: it is too early to abandon embryonic stem cell research in diabetes. Opponents of such experiments have made the use of adult stem cells a rallying cry. Sadly, we may not have the luxury of that option.

References
1. Holland, Góñez and Harrison. Progenitor cells in the adult pancreas. Diabetes/Metabolism Research and Reviews. Volume 20, Issue 1, Date: January/February 2004, Pages: 13-27
2. Yuval Dor, Juliana Brown, Olga I. Martinez, Douglas A. Melton. Adult pancreatic -cells are formed by self-duplication rather than stem-cell differentiation. Nature Volume 429, Pages 41 – 46 (06 May 2004.)