Science Editor

In many minds, regenerative medicine is synonymous with stem cells. And Type I diabetes, which is due to the lack of a single cell type - insulin-producing pancreatic beta cells - is a good candidate disease for the approach.

Recent findings suggested, though, that for replacing beta cells, the exact type of regenerative medicine may turn out to be different than expected.

In the May 2007 issue of Developmental Cell, scientists from the University of Pennsylvania School of Medicine report that in animal studies, they were unable to track down an adult stem cell that divides to produce insulin-producing pancreatic beta cells; instead, most, if not all, adult beta cells can continue to divide slowly.

Senior author Jake Kushner, a pediatric endocrinologist at The Children's Hospital of Philadelphia, described the implications of the study: "This research tells us that we need to better understand what regulates the growth of beta cells, rather than searching for adult stem cells that give rise to beta cells," he said. (A recent study that used stem cell transplantation for the treatment of Type I diabetes used hematopoietic, or blood-forming, stem cells, which replace the immune system rather than beta cells.)

The authors investigated cell fates by extending a labeling technique known as thymidine analogue labeling. Thymidine is one of the four bases that make up DNA. By sequentially using two different thymidine analogues, the authors could distinguish between cells that had undergone several recent divisions - which would be indicative of a stem cell - and more slowly dividing cells.

Using their lineage tracing method, the authors were able to see adult progenitor cells in the intestines and skin, confirming that the method was able to identify stem cells.

But in the pancreas, such putative stem cells were nowhere to be seen. "Remarkably, we observe no contribution to adult beta cell mass by specialized progenitors or stem cells," the authors wrote in their paper. Instead, "we show that adult beta cells exhibit equal proliferation potential and expand from within a vast and seemingly uniform pool of mature beta cells."

The authors also found that even though most, if not all, adult beta cells appear to be able to divide, they apparently have natural brakes on how rapidly they are able to do so. In what the researchers termed a "replication refractory period," beta cells appeared unable to divide more than once every few months under normal circumstances.

Kushner told BioWorld Today that so far, the duration of the refractory period is unclear, but it appears to be between three and eight months. Studies to pin the timing down more exactly are ongoing, as are investigations into whether other slowly dividing adult tissues use a similar mechanism. The refractory period was shortened, but not abolished, under special circumstances - both in pregnancy and if part of the pancreas was removed surgically.

Since not all beta cells are destroyed in patients with Type I diabetes, the findings suggested that stimulating those residual beta cells to divide and conquer diabetes might be a viable therapeutic approach, though the refractory period they describe makes clear that the approach will have its own challenges - or as the authors put it, "efforts to determine the molecular regulation of adult beta cell proliferation are particularly strategic."

In the meantime, the method itself also opens new possibilities for lineage tracing. Current lineage tracing over several cell divisions requires the use of cell-surface markers, which limits the cell types that can be studied. Double labeling obviates the need for such markers, making it possible to study the lineage of a much wider group of cells, and search for dividing cells in an "unbiased" manner, the authors wrote. They foresee application in lineage tracing, but also in the study of stem cell divisions. The growth of cancer cells and the response to chemotherapy could be studied using the technique as well.