Changing cellular career paths.

Every year over 13,000 young people are diagnosed with type 1 diabetes, an autoimmune disease where the bodies own defense system turns on the beta cells of the pancreas that produce insulin.  While the development of insulin therapy has enabled many  type I diabetics to live relatively normal lives there is as yet no cure for the disease.  In recent years efforts have been made to restore insulin producing cells to the patients so that they do not need to take insulin.

Transplants of insulin producing cells have had some success in clinical trials but have a huge disadvantage in that the patients need to take immunosuppressive drugs to stop their immune system attacking the “foreign” cells; such drugs have undesirable side effects.

Among several approaches being examined to overcome this problem is the use of iPS stem cells which are obtained from the patient themselves, and therefor will not provoke an immune response.  The theory is that these stem cells can be programmed to develop into insulin producing cells and then transplanted back into the patient. While very promising iPS cell research is at an early stage, so it will take a lot of time and research before it can be tried in human patients. In particular there are worries that the very flexibility that allows iPS cells to develop into many cell types might in some circumstances cause cancers.

Inspired by the iPS cell research and the ability of mature cells of animals such as salamanders to change into other cell types during regeneration of injured limbs, Douglas Melton and colleagues at Harvard decided to see if it was possible to reprogram adult cells to become insulin producing cells without going all the way back to stem cells (1).

Image: Understanding Animal Research

Image: Understanding Animal Research

They first screened over a thousand genes that coded for proteins known as transcription factors which regulate the functions of cells to see which are expressed in the developing mouse pancreas, and compared that information to mouse gene knock-out studies to identify nine genes that coded for transcription factors that were important to the development of insulin producing beta cells.  Having identified these genes they needed to know what combination of these genes could convert non insulin producing cells of the fully developed adult  pancreas into insulin producing cells. If such a combination could be identified they also needed to find out if the new insulin producing cells could survive in the pancreas, or would they quickly revert to being non-insulin producing cells.  To do this they used an adenovirus vector which when injected into the mouse pancreas carries new genes into the cells where they then become active.

With the viral vector they studied several combinations of genes, and after trying several combinations they identified three transcription factor genes – Ngn3 (also known as Neurog3) Pdx1 and Mafa – which could together turn pancreatic cells into insulin producing cells.  This was despite the fact that the new insulin producing  cells were outside the beta islets where insulin producing cells are normally found. These new insulin producing cells were still present several months after the mice were treated, and when this technique was used in diabetic mice whose pancreatic beta cells had been destroyed it improved their ability to control their blood sugar levels.  They also found that the virus didn’t spread to other tissues, an important observation that suggests the technique will be safe.  Perhaps most importantly they found that the pancreatic cells did not change into stem cells, but instead changed directly from one type of pancreatic cell to another.

This work has obvious implications for the development of cures for type one diabetes, though to be sure there’s a lot of work to be done yet before it can be tried in humans.  However the most important aspect of this research is that it demonstrated for the first time that it is possible to change cell of one type into another type in adult tissue, a discovery that has great implications for the future of regenerative medicine.

Cheers
Paul


1) Zhou Q. et al “In vivo reprogramming of adult pancreatic exocrine cells to bold beta-cells” Nature, published online 27 August 2008, DOI: 10.1038.

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