Reprogramming: A Primer

Reprogramming: A Primer

Reprogramming is taking one type of cell in the body and converting it into a different type. In diabetes research, the goal is to end up with a beta cell that produces insulin in response to glucose.

While many cell types have been investigated for their reprogramming potential, recent studies led by JDRF-funded scientists demonstrate that alpha cells are a particularly attractive target. Alpha cells, like beta cells, are found in the islets of the pancreas and secrete hormones. Beta cells produce the hormone insulin, which lowers blood sugar levels. Alpha cells produce the hormone glucagon, which raises low blood sugar to normal levels.

Last year, a group of researchers at the Max-Planck Institute in Germany showed that they could reprogram alpha cells to beta cells in mice. They did so by forcing the expression of a gene normally restricted to the beta cells, Pax4, in alpha cells. The newly formed beta cells were functional and protected the mice from diabetes.

“The interesting feature of this discovery is that such transformed beta cells are functional and can reverse the consequences of chemically-induced type 1 diabetes in a mouse,” said Dr. Patrick Collombat, who is now working at Inserm in Nice, France, one of the study’s co-leaders.

The study shed new light on the properties of beta cells. “This study provides strong evidence that beta cells are more ‘plastic’ than previously assumed and that type 1 diabetes can potentially be cured using a patient’s own cells,” said Dr. Ahmed Mansouri, who co-led the study.

Another advance was announced earlier this year when a research team in Switzerland said it had been able to convert alpha cells to beta cells without any genetic manipulation of the alpha cells. This has important implications for the possibility of using reprogramming to treat people; genetic manipulation involves processes that don’t easily translate into therapies for people. In the Swiss study, scientists first engineered a mouse susceptible to a toxin that would destroy only their beta cells.

When the mice were exposed to the toxin, more than 99 percent of their beta cells were gone after 15 days of treatment. The scientists kept the mice alive with insulin. They found that beta cells recovered over time and that many of the new beta cells arose from alpha cells that had reprogrammed into beta cells. Eventually, the mice no longer needed insulin replacement to stay alive. “We observed that if we kept the mice alive with insulin, the pancreas can spontaneously reconstitute up to 10 percent of the normal beta cell mass over several months,” said Dr. Pedro Herrera at the University of Geneva, who led the study.

The Geneva team’s results are the first to show that beta cell reprogramming can occur spontaneously, without scientists altering specific genes. “The big breakthrough is showing that alpha-to-beta cell reprogramming can be a natural, spontaneous process,” Dr. Rakeman said. This breakthrough provides significant information for developing treatments. “This study opened up the possibility of reprogramming not only as an interesting biological phenomenon, but as something that we could harness therapeutically,” Dr. Rakeman said. “If we can understand the signals that are triggering this conversion, it will open up a whole new potential strategy for regenerating beta cells in people with type 1.” Dr. Herrera agrees:

“The important message is that the adult pancreas can regenerate through mechanisms that we didn’t think were possible,” he said. “We can imagine ways to use this knowledge to foster this process of reprogramming in people with diabetes.”

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