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Researchers Discover Unexpected Source of Insulin-Producing Cells

By Nancy Touchette

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Stem Cells

Many diabetes researchers have been pinning their hopes on stem cells as a way to regenerate the insulin-secreting cells of the pancreas in people with type 1 diabetes. But a study by Harvard scientists disputes the notion that adult stem cells replenish damaged cells in the pancreas.

Instead, the research, done in mice, shows that new insulin-secreting cells, known as beta cells, arise when beta cells that already exist in the pancreas replicate. The researchers suggest that to treat diabetes, the focus should be on the beta cells themselves and how to get them to replicate to restore function to the pancreas.

“This is an intriguing and provocative study,” says Joel Habener, who studies pancreatic cells at Massachusetts General Hospital in Boston. “It has turned current thinking upside down and will stimulate thinking among people looking for cellular therapies to treat diabetes. It’s wonderful.“

The research finding, published in this week’s Nature, is surprising because mature cells have not been considered capable of replicating. Only immature cells such as stem cells are believed to have the capacity to multiply.

Early attempts to coerce mature beta cells to replicate in the test tube have been unsuccessful. So, researchers had largely turned their efforts to finding stem cells in the pancreas in hopes that they could replace the beta cells destroyed by disease.

Type 1 diabetes, also known as juvenile diabetes, occurs when a person’s own immune system attacks the beta cells of the pancreas. The cells, clustered in islets in the pancreas, secrete insulin, a key hormone that controls glucose uptake in cells throughout the body.

People with type 1 diabetes, which usually develops in childhood, must inject themselves with insulin several times a day for their entire lives. Islet cell transplants, using tissue from donor cadavers, have been successful in curing the disease, but there is only enough tissue to treat one in 500 patients.

“There has been a well-founded emphasis on stem cells and progenitor cells,” says Ken Zaret of Fox Chase Cancer Center in Philadelphia, who wrote a commentary that appeared with the study. “But we are now learning that fully mature cells have capabilities we have not appreciated. This certainly goes against the grain of most people studying regeneration of the pancreas.”

In the study, Douglas Melton and his colleagues at Harvard University in Cambridge, Massachusetts, “tagged” beta cells in mice by inserting a specially constructed gene. The inserted gene allowed them to determine whether new cells came from pre-existing beta cells or from some reservoir of stem cells. They traced the cells for up to a year in untreated mice and in those who had a part of their pancreas removed.

Melton found that beta cells already in the pancreas were the source for replenishing cells lost through normal wear and tear, and for the replacement of cells following extensive damage to the pancreas. The researchers found no evidence of stem cells in the pancreas.

No one has really paid much attention to the ability of the beta cell to replicate, Melton said in a statement to the press. “This work shows the cells to have a significant proliferative capacity that could be clinically useful.”

Melton says the next step is to find ways to trigger the replication of beta cells in patients who still have residual cells. For people who have had all their beta cells destroyed by disease, the only source of new cells may be embryonic stem cells, which can be coerced into forming beta cells that cluster in structures known as islets, similar to those found in the pancreas.

Melton, whose two children are both afflicted with type 1 diabetes, has been named head of Harvard’s new Stem Cell Research Institute, which will focus on developing sources of stem cells, including embryonic stem cells. He recently used private funds to generate 17 embryonic stem cell lines. Under current Bush policy, it is illegal to use federal funds to generate new lines of embryonic stem cells.

Denise Faustman of Massachusetts General Hospital in Boston says Melton’s study is significant because it shows that the pancreas can regenerate itself.

“Four years ago, we weren’t even allowed to say the word ‘regenerate’ when talking about restoring the cells of the pancreas,” says Faustman. “No one believed it. But the field is moving rapidly and now it appears that there may be many routes to replace these cells.”

Researchers are following an array of paths toward replacing beta cells in the pancreas. Some studies suggest that stem cells in the bone marrow or spleen can replace damaged pancreas cells, while other studies point to a reservoir near a structure in the pancreas known as a duct.

“Most investigators are still going to look for stem cells,” says Habener. “They’re not ready to throw the baby out with the bathwater. But new concepts are always met with skepticism. Eventually out the controversy, comes enlightenment.”

Dor, Y. et al. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41-46 (May 6, 2004).
Zaret, K. Self-help for insulin cells. Nature 429, 30-31 (May 6, 2004).

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