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A Step Closer to Regenerating Beta Cells

Posted: Wednesday, July 22, 2009

US scientists have come a step closer to finding a way to help treat people with diabetes by reactivating their own insulin-producing beta cells in the pancreas. They discovered a hitherto unknown role for a well known protein: it helps immature endocrine systems generate new pancreatic islet cells, which include the insulin-producing beta cells.

The study, which was done on mice, was the work of senior author Dr. Doris Stoffers, Associate Professor of Medicine at University of Pennsylvania School of Medicine, Philadelphia.

Both Type 1 and Type 2 diabetes are caused by a lack of insulin-producing beta cells. While in theory it should be possible to transplant beta cells grown from embryonic or other types of stem cells, in practice no one has managed to do it effectively.

Stoffers and colleagues mapped each stage of development up to mature beta cells, including the genetic pathways. They hope that one day these steps can be replicated so that beta-cells can be grown in the lab, and then in the patients themselves.

Stoffers, said that, "The protein, Pdx1, is a pivotal molecule in the regulation of beta-cell development and we hope this type of information could help in efforts to generate beta-cell replacements for the treatment of diabetes."

Scientists already knew that Pdx1 helped control the development of the pancreas and the maturation of adult beta cells. For instance, previous studies have shown that when mice lose a single copy of the gene that codes for the protein they develop diabetes, and when they lose two copies their pancreas doesn't form at all.

In this new study, Stoffers and her colleagues showed that Pdx1 also has a role in precursor beta-cell formation in the developing embryo. This process is controlled by a DNA-binding transcription factor called neurogenin-3 or Ngn3, which in turn is controlled by four other proteins, Sox9, Foxa2, Hnf6, and Hnf1b.

Their key discovery was finding out that Pdx1 binds directly to the Ngn3 gene to coordinate the gene expression of these proteins. Stoffers said that if they could understand how Pdx1 works normally, then they might be able to "apply that information to faithfully and efficiently push the cells down the pathway to ultimately generate beta cells that may be used clinically."

Stoffers and colleagues were particularly interested in the C terminus end of Pdx1, whose role in beta cell development was still unclear, and yet in certain diseases this part is mutated. So they bred mice lacking the C terminus -- in effect their Pdx1 proteins were shorter.

They found that when both copies of the Pdx1 gene were short of their C terminus, the mice grew a pancreas but quickly developed diabetes. When they looked more closely they found that the mice had no endocrine cells, including beta cells. Stoffers said this led them to conclude that, "The defect was at an early cell, or precursor, stage."
 
"Specifically, in the formation of Ngn3-expressing endocrine progenitor cells," Stoffer added.

Further study of the molecular properties of the protein in the mutant mice led them to conclude that Pdx1 controls the development of precursors to endocrine cells by binding directly to the Ngn3 gene, controlling how it is expressed. It also binds directly and controls other endocrine cell genes.

"Pdx1 not only directly regulates Ngn3, it also indirectly regulates it by controlling the regulatory network of Sox9, Foxa2, Hnf6, and Hnf1b," said Stoffers.

Stoffers and colleagues now want to find out if the same molecular pathways take place in humans, and so discover if Pdx1 plays the same role.

"It is likely that the mechanisms are the same, but we would like to directly test that," she said.

Source: Diabetes In Control: "The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice." Authors: Jennifer M. Oliver-Krasinski, Margaret T. Kasner, Juxiang Yang, Michael F. Crutchlow, Anil K. Rustgi, Klaus H. Kaestner, Doris A. Stoffers. J. Clin. Invest.Published in Volume 119, Issue 7, pp 1888-1898 (July 1, 2009), doi:10.1172/JCI37028.

 
 
 
 
 
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