January 24, 2006
‘Cocktail’ Helps Adult Stem Cells Thrive in Lab
Discovery could aid bone marrow transplants, gene therapy, researchers say
Scientists have discovered a "cocktail" of growth factors that expands the number of stem cells they can grow in the laboratory at least 10 times beyond what anyone has been able to do before.The technique, if replicated in humans, could greatly enhance the effectiveness of bone marrow transplants, and may even help refine gene therapy, the researchers said.
Their findings appear in the Jan. 22 online issue of Nature Medicine.
"This is a tremendous finding for the field," said Bruce A. Bunnell, an associate professor of pharmacology at the Center for Gene Therapy at Tulane University Health Sciences Center in New Orleans. "This is a significant advancement that can probably go into use right away."
Tulane's gene therapy center is the only National Institutes of Health-sponsored organization to distribute adult stem cells to other academic researchers around the world.
"It's important work, clearly, because it demonstrates continuing research to increase expansion of adult stem cells," added Paul Sanberg, director of the University of South Florida Center for Aging and Brain Repair in Tampa. "It's an efficiency question."
Stem cells from bone marrow or cord blood (from the umbilical cord and placenta) are used to treat patients with certain blood diseases, including some cancers. The problem has been collecting enough stem cells for the treatments.
"The practical problem is for a lot of bone marrow transplants you need more stem cells than you can get," explained senior study author Harvey Lodish, a member of the Whitehead Institute for Biomedical Research in Cambridge, Mass. "It's a numbers game."
"One of the major issues for hematopoietic [stem cells which go on to form blood cells] and bone marrow transplantation has been the inability to get sufficient numbers of cells because they just don't want to grow in the laboratory," Bunnell added. "In general, we get maybe a two- to five-fold expansion, and for most patients and most transplants you need many more cells. The ability to generate many more cells would more than likely significantly enhance the efficiency at which engraftment occurs. The ability to go from five-fold to 30-fold is a tremendous advancement."
Researchers have been on a quest to find better ways to use adult stem cells, largely because they are free of the ethical baggage surrounding embryonic stem cells.
Here, researchers found, in mice, a group of cells separate from stem cells that seemed to exert an effect on stem cells, helping them multiply.
How did these "support cells" do it?
Chengcheng Zhang, lead author of the paper and a postdoctoral researcher in Lodish's lab, was able to show that these cells had specific genes that were activated and encoded for growth factor proteins. One such growth factor, IGF-2, had already been discovered. IGF-2 contributed to an eight-fold growth in stem cells.
Zhang and Lodish were assisted in this experiment by Kathleen Xie, then a 16-year-old high-school student. Xie, now 17, is attending MIT as a freshman.
Now, Zhang, Xie and the other authors can add two more growth factors to the roster: Angiopoietin-like 2 and -3. When these were combined with IGF-2 and added to hematopoietic stem cells, the growth was 30-fold.
Lodish's lab is in the process of testing the findings in human cells. "There are some immediate experiments to see if we can use the same cocktails of growth factors to expand cord blood cells or human stem cells," Lodish said.
The work has several potential applications. One is to increase the efficiency of existing bone marrow transplants. "This would increase the chance of getting a good transplant," Lodish said.
Another relates to gene therapy. Currently, a healthy version of a gene is introduced into a group of the patient's stem cells via a virus. The stem cells, now with the correct version of the gene, are re-administered to the patient. With this method, however, scientists can't control where the virus ends up and, in several cases, the virus activated cancer-causing genes. For this reason, the researchers said, the U.S. Food and Drug Administration is not currently approving any gene therapy clinical trials.
But the new discovery might enable scientists to multiply the patient's stem cells in the lab, and run tests to see if the virus ends up in the right place. The bad cells could then be thrown away, and the good ones re-administered to the patient.
"Right now, the techniques for gene therapy are kind of brute force. You put the gene in and hope it goes into the right place. There's no selection," Lodish said. "What we would like to do is put the gene into stem cells, grow them and watch them to be as sure as one can be that we've got the right gene into the right cells and nothing untoward has happened."
The new findings also holds implications for basic science. "We want to understand how stem cells make this decision to differentiate or stay stem cells," Lodish explained. "What signals do they get? These are big questions, difficult questions, and we need to answer them. These are hard questions, but slowly we'll get the ability to answer them."
The National Institutes of Health has more on stem cells.