November 21, 2003
MIT Technique To Produce Large Numbers Of Adult Stem Cells

An MIT researcher has discovered a way to produce large numbers of adult stem cells.

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.

The idea here is that when an adult stem cell divides normally the result is one adult stem cell as well as one differentiated cell to supply to the target tissue that needs a new cell. The problem is that for therapeutic purposes what is needed is a way to tell an adult stem cell to divide to create two adult stem cells and then to divide to each create two more adult stem cells and so on until many times more adult stem cells are available. Only then in most therapies would there be enough stem cells to do cell division to produce the needed amount of differentiated cells for target tissues.

“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.

Actually, some adult stem cell types can become several different differentiated (i.e. fully specialized) cell types. But any one kind of adult stem cell can not become all cell types. Though at some point in the future expect to see techniques developed that will make it possible to instruct adult stem cells to become more kinds of differentiated cell types. A simple rule to remember that FuturePundit thinks by: Matter becomes steadily more manipulable and transformable to achieve more kinds of outcomes as technology advances.

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 absence 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.

It sounds like he has a technique that suppresses p53 and that as a result the cells start dividing in a way that each division produces two adult stem cells.

What is needed for use in conjunction with this technique are better ways to test DNA quality noninvasively. There are many genes which, if they mutate, put a cell one step closer to becoming a cancer. To develop safe rejuvenation therapies what we need is a way to test stem cells and weed out cells that have accumulated mutations in genes that are crucial for cell division control. Then aged adult stem cell reservoirs could safely be replenished with cells that are at very low risk of going on a rampage of cancerous growth.

One other point: It would be interesting to know whether this research team tested the stem cells induced to divide in this manner to discover whether the cells became any less differentiated as a result of being induced to make two cells that are still stem cells. Would continued division of this sort result in daughter cells that do not replicate the methylation patterns and other epigenetic state that the adult stem cells started out with?

Update: The ability to replicate adult stem cells would be useful for use in leukemia treatments and other treatments that are already being practiced today. Keith Sullivan M.D. of Duke University explains the difficulties involved in collecting stem cells today.

Sullivan explains that there are two ways to donate stem cells. "The first is from one's own bone marrow," he says. "This typically requires an hour or two in the operating room under anesthesia to have stem cells collected by a mini-surgical procedure in the area of the hip bone.

"The other option is to collect blood for stem cells, which is not the same as simply giving blood. Stem cells are quite rare in circulating blood, so what's needed is three or four days' worth of growth factors and shots to increase the percentage of stem cells. These stem cells are then collected on a pheresis machine, which collects the stem cells and gives the red and white platelets back."

Sullivan also notes one other important source of stem cells: "If a woman is pregnant and wishes to donate some of the blood in the umbilical cord at the time of birth, these cells have the advantage of being early, undifferentiated cells. Therefore they have less potential for reactivity and adverse complications."

If stem cells could be easily replicated then just a few could be removed from the blood and grown up to large quantities. This might eliminate the need for surgery or the administration of a few days worth of growth factors.

Share |      Randall Parker, 2003 November 21 02:50 PM  Biotech Organ Replacement


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