September 8, 2008

Rare Insulin-Producing Cells Created from Adult Mouse Cells

Microscope image of multicolored cells in a mouse pancreas is image of an adult mouse pancreas shows former exocrine cells (green) that have been reprogrammed to become beta cells that produce insulin (red). The blue streaks are blood vessels, which are remodeled by, and lie close to, the new, insulin-producing beta cells.Joe Zhou, Melton Lab, Harvard Stem Cell Institute

By tweaking just 3 genes in living mice, scientists have transformed common adult pancreas cells into a rarer type of cell that produces insulin. The reprogrammed cells generated enough insulin to bring down abnormally high blood sugar in diabetic mice. The study shows that mature cells can directly change into new cell types without first reverting back to a stem cell state.

Researchers have long searched for ways to create cells to help repair damaged tissues or replace cells lost to disease. One approach has used embryonic stem cells, which have the potential to transform into all cell types. Researchers in Japan developed a less controversial alternative 2 years ago. By inserting only 4 genes into adult mouse skin cells, they pushed the cells back to their more versatile stem cell stage. But both techniques still require figuring out how to coax stem cells into the desired type of therapeutic cell.

In the new study, Dr. Douglas Melton, codirector of the Harvard Stem Cell Institute, and postdoctoral researcher Dr.Qiao Zhou skipped the need for stem cells altogether by directly reprogramming adult exocrine cells, which make up about 95% of the pancreas, into insulin-secreting beta cells, which comprise just 1% of a normal pancreas. Their research, reported in the August 27, 2008, advance online edition of Nature, is supported by NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Howard Hughes Medical Institute and the Harvard Stem Cell Institute.

The researchers sorted through more than 1,100 transcription factors—proteins that switch genes on and off—and identified at least 20 that are expressed in mature beta cells. They selected 9 promising ones and inserted their genes into adenoviruses, which deliver genes into exocrine cells. They then injected a mix of the viruses into pancreases of living mice. One month later, the mice had more insulin-producing cells in their pancreases. By removing one gene at a time from the mix, the researchers were able to zero in on a combination of just 3 transcription factors that could convert the globular exocrine cells into smaller, spindle-shaped beta cells that look and function just like other beta cells.

When the researchers injected the engineered adenoviruses into mice that were deficient in beta cells, newly formed beta cells secreted enough insulin within 2 weeks to reduce the animals' blood sugar to near-normal levels. Insulin production and blood sugar control continued for more than 9 weeks.

“I would say this is a step toward eventually developing a treatment for both type 1 and type 2 diabetes, in that both conditions have a deficiency in the insulin-producing beta cell,” Melton says.

This study sets the stage for developing clinically useful cells by reprogramming adult cells. However, Melton cautions that more research is needed before such cells could be tested in humans. He also notes that reprogrammed cells cannot fully replace research into embryonic stem cells and other types of stem cells. “These cells still have much to teach us about the mechanisms of disease and human development,” Melton says.

— by Vicki Contie

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