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CAMBRIDGE, Mass. -- In a finding that may help create unlimited quantities of therapeutically valuable adult stem cells, an MIT researcher fortified adult rat liver stem cells with a metabolite that allows them to multiply like embryonic stem cells.
In the absence of the metabolite, the cells revert to acting like normal adult stem cells, which produce differentiating cells without increasing their own numbers. Stem cells proliferating unchecked can cause cancer.
"If we want to do cell replacement therapy with stem cells, we have to be able to monitor them and avoid mutations that cause tumors in people," said James L. Sherley, associate professor of biological engineering in MIT's Biotechnology Process Engineering Center, Center for Environmental Health Science and Center for Cancer Research.
Embryonic stem cells can become virtually any human tissue or organ, offering potentially powerful treatments for damaged or diseased organs, spinal injuries, neurological diseases and more. Unlike embryonic stem cells, which exist only during early prenatal development, adult stem cells create new tissues throughout our lifetimes. Their potential to produce mature tissue cells may be limited to cells of the tissues in which they reside.
The Bush administration has restricted stem cell science involving human embryonic stem cells, though these rules do not apply to adult stem cells. But biomedical applications using adult stem cells have been limited by the fact that adult stem cells are notoriously hard to isolate and multiply.
In a recent issue of the journal Biotechnology and Bioengineering, Sherley demonstrated a method that could produce new lines of adult stem cells for research and potential therapies.
Adult stem cells are thought to exist in at least 13 body tissues, but Sherley believes that virtually every tissue and organ, including the brain, has some innate ability to regenerate. "We are not static beings," he said. "Our tissues turn over constantly and there must be cells that remember the form" of the original organ.
Adult stem cells constantly produce new skin, intestinal lining, red blood cells and more. They are remarkably versatile: adult stem cells in bone marrow, for instance, can be channeled to become fat cells, cartilage-forming cells or bone-forming cells.
One of the problems of working with adult stem cells is that they are very rare and difficult to isolate. Researchers who attempt to grow adult stem cells in the laboratory find that they cannot increase the number of stem cells in culture, because when adult stem cells divide, they produce both new replacement stem cells and regular cells, which quickly proliferate and vastly outnumber the stem cells. Adult stem cells divide to replace themselves and create daughter cells, which either differentiate immediately or divide exponentially to produce expanded lineages of differentiating cells.
In previous work, Sherley created cells that divide the way adult stem cells do -- by hanging onto their original DNA and passing copies on to the next generation of daughter cells. The theory goes that through this unique pattern of chromosome segregation, adult stem cells avoid mutations that may arise from DNA replication errors.
DIVIDING IN TWO
Sherley has dubbed this pattern asymmetrical cell kinetics because the cells don't divide symmetrically into two identical cells. His new approach to growing adult stem cells suppresses this asymmetrical mechanism. He calls it SACK (suppression of asymmetrical cell kinetics).
Through SACK, Sherley created a way to make cells that were dividing asymmetrically like stem cells revert to dividing symmetrically. This involves manipulating biochemical pathways regulated by the expression of the p53 gene (tied to many human cancers) by exposing cells to certain nucleotide metabolites that activate growth regulatory proteins. In the presence of the metabolites, cells are converted from asymmetric cell kinetics to symmetric cell kinetics.
When p53 is switched on, cells grow like adult stem cells. While others have attempted to alter adult stem cells genetically to force them to duplicate themselves, "what's neat about this approach is that we are regulating the biochemistry of the cell, not changing its genetics," Sherley said.
In addition to Sherley's team, collaborators include researchers at National Taiwan University Hospital and members of Professor Linda Griffith's laboratory at MIT.
This work is supported by the Defense Advanced Research Projects Agency (DARPA), the MIT Charles E. Reed Faculty Support Fund, the National Science Foundation Engineering Research Center and the MIT-duPont Alliance.