We tend to regard the mature cells in our bodies as having reached their final destinations - if they become specialists, like heart or brain cells, they remain that way. But more and more, research is showing this is not always the case. And fortunately for people with type 1 diabetes, a recent study reports on similar transformational prospects for cells in the pancreas.
Juvenile Diabetes Research Foundation (JDRF)-funded researchers led by Dr. Pedro Herrera (pictured) at the University of Geneva in Switzerland have shown that what are called "alpha cells" in the pancreas - specialized cells that do not produce insulin - can spontaneously convert into insulin-producing beta cells. And while these changes took place under very specific experimental conditions in mice, the study advances the prospect of regenerating beta cells as a cure for type 1 diabetes. It points to the unexpected "plasticity," or potential, of pancreas cells to adapt and produce insulin when they must - in this case, when the beta cells that normally produce insulin in those mice were entirely killed off. Ultimately, scientists may be able to harness this conversion potential to regenerate beta cells in people with diabetes.
For the experiments, the researchers used mice in which nearly all of the beta cells are rapidly destroyed. They made two important discoveries - first, that beta cells will spontaneously regenerate after near-total beta cell destruction, and second, that most of these regenerated beta cells come from alpha cells that reprogrammed, or converted, into beta cells. Alpha cells normally reside alongside beta cells in the pancreas and secrete a hormone called glucagon, which works to oppose insulin in regulating levels of sugar in the blood. Alpha cells are not attacked by the autoimmune processes that destroy beta cells and cause type 1 diabetes.
In the experiments, the insulin-producing beta cells were slowly and spontaneously restored, eventually eliminating the mice's need for insulin replacement.
According to Andrew Rakeman, JDRF Program Manager in Beta Cell Therapies, the big breakthrough in Dr. Herrera's work is showing that alpha-to-beta cell reprogramming can be a natural, spontaneous process.
"If we can understand the signals that are triggering this conversion, it will open a whole new potential strategy for regenerating beta cells in people with type 1 diabetes," he said. "It appears now that the body can restore beta cell function either through reprogramming alpha cells to become beta cells or, as has previously been shown by other researchers, by increasing the growth of existing beta cells. This new path may be particularly useful in people who have had diabetes for a long time and have no, or very few, remaining beta cells."
Dr. Herrera's team genetically engineered the mice to be susceptible to a toxin that would destroy only their beta cells. When the mice were exposed to the toxin, the beta cells were rapidly and efficiently destroyed - greater than 99% just 15 days after treatment. To then track the source of newly regenerated beta cells, the researchers used another genetic manipulation to label mature alpha cells (and their descendents) with a fluorescent protein. This "genetic lineage tracing" approach allowed the scientists to track the fate of the alpha cells and their progeny. The presence of fluorescently labeled beta cells in the mice that recovered insulin production was conclusive evidence that alpha cells had reprogrammed into beta cells.
The Geneva researchers pointed out that the critical factor in sparking the alpha-to-beta cell reprogramming was removing nearly all the original insulin-producing cells in the mice. In mice whose loss of beta cells was more modest, the researchers found no evidence of regeneration, and less alpha cell reprogramming. "The amount of beta-cell destruction appears to determine whether regeneration occurs. It influences the degree of cell plasticity and regenerative resources of the pancreas," they explained.
Also noteworthy is that Dr. Herrera's results are the first to show that beta cell reprogramming can occur spontaneously, without genetic manipulation. Previous efforts to reprogram non-beta cells into beta cells relied on altering genes - processes that cannot be easily translated into therapies for people.
Illustration: University of Geneva.
Juvenile Diabetes Research Foundation International News Release (04/05/10)
Medical News Today (04/06/10)
Science Daily (04/06/10)
Science News (05/08/10)
Abstract (Nature: 464, 1149-1154 (04/22/10))