Stem cells ‘reprogrammed’ to produce insulin?

VANDERBILT (US)—The answer to that question could radically change the future of diabetes treatment. Recent findings suggest scientists are closer to identifying a way to reprogram cells in the laboratory and inject those cells back into the body to repair damage caused by disease.

Scientists at Vanderbilt University have been investigating how this radical approach could be used to cure diabetes. They’re excited about what they’re seeing in the lab.

“I think we’ll be putting pancreatic beta cells that have been made in a dish into people within 10 years,” says Mark Magnuson, director of the Vanderbilt University Center for Stem Cell Biology.

Sounds like science fiction?

Magnuson and others might have agreed—until last year, when several provocative reports were published. By inserting various combinations of genes, scientists at Kyoto University in Japan and the University of Wisconsin, Madison, reported that they had “induced” human skin cells to revert to an embryonic-like state of “pluripotency”—capable of turning into any other kind of cell.

Injections of these so-called induced pluripotent stem (iPS) cells have been shown to improve symptoms of sickle cell anemia and Parkinson’s disease in experimental mice and rats.

Last year also provided evidence that the pancreas can be “coaxed” into repairing itself. A team of Belgian and French researchers reported that, with the help of a factor called neurogenin3, injured adult mouse pancreas can generate new beta cells from immature “progenitor” cells.

“Everybody had been thinking for the past several years that . . . you wouldn’t make any new ‘baby’ insulin-producing cells from a progenitor,” says Vanderbilt developmental biologist Maureen Gannon. “And now there’s evidence that you can reactivate that program. That, to me, is really exciting.”

These findings are “hugely radical, unpredicted,” Magnuson adds. “They change the paradigm about the plasticity of every cell in the body . . . [implying that] you can follow the developmental path, go way back to the beginning, and then come forward to whatever cell you like.”

Reprogramming a patient’s cells to produce insulin would provide a welcome alternative to transplanting pancreatic tissue from other human or animal donors, a procedure limited both by the lack of donor tissue and by the need to suppress the patient’s immune system to prevent transplant rejection. It also could avoid the need to harvest another, more controversial source of stem cells, those derived from human embryos.

However, the virus used by the Japanese scientists to insert the “reprogramming” genes also triggered formation of tumors in mice. “This is not a trivial issue,” cautions Alvin Powers, a leader in the study of pancreatic biology and islet transplantation who directs the Vanderbilt Diabetes Center.

And even if the pancreas can be induced to generate new beta cells, or if skin cells could be “reprogrammed” to produce insulin, that does not solve the underlying problem of type 1 diabetes—misguided attack by the body’s immune system that destroys the beta cells.

Christopher V.E. Wright, who directs the Vanderbilt Program in Developmental Biology, agrees. “What is the nature of the autoimmune problem in diabetes?” he asks. Is the immune system of these patients dysfunctional, such that it mistakes normal tissue for a germ and attacks it? Or could the beta cell be displaying the wrong “badge” on its surface, one that attracts “friendly fire?”

One way to answer these questions is to figure out the steps that lead to the development of the beta cell, and then to try to determine whether that differentiation program is “messed up” in the patient with diabetes.

Wright believes developmental biology may hold the keys to unlocking the mystery of this ancient disorder.

“One of my strongest beliefs is that developmental biology and cancer biology and aging and all forms of inherited disease are basically the same process,” he says.
“Because the study of developmental biology involves trying to understand the generation of life, it uses and develops completely novel principles and tools and ways of looking at things to understand how multiple signaling pathways are used by cells to talk to each other in complicated ways.

“And because of that, it ends up being one of the most pioneering of disciplines.”

A major goal now is to learn all the steps needed to direct a stem cell to become a beta cell. Wright visualizes a day when scientists will be able to create “personalized” pluripotent stem cells from the tissues of a patient with diabetes, and then kick them forward to see if they develop into beta cells completely normally, or display abnormalities at a specific stage of formation.

“That is what stem cell biology has done for us so far,” adds Magnuson, the Earl W. Sutherland Jr. Professor of Molecular Physiology & Biophysics. “It has given us a brand new view of what is possible.”

To read more about this research, visit www.mc.vanderbilt.edu/lens/article/?id=191.

Vanderbilt University news: www.vanderbilt.edu/news

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