Scientists in the Clinical Research Division have described a technique that could rapidly increase the number of blood-forming stem cells after transplantation and speed up the process of engraftment — it's a strategy that holds promise for breaking down obstacles to cord-blood transplants and for gene therapy.
Dr. Hans-Peter Kiem and colleagues enhanced stem cells with a gene called HOXB4 in a clinically relevant animal model in hopes of being able to rapidly increase the number of blood-forming cells.
"We found that by using this particular gene, we could indeed expand blood-renewing cells," said Kiem, who also works with Center researchers Drs. Irwin Bernstein and Colleen Delaney to overcome issues currently limiting the use of cord-blood stem cells. Study results were published in the May issue of the journal PLoS Medicine.
Use of cord-blood stem cells
The new method, which could facilitate the use of cord-blood stem cells for transplantation, will be tested next specifically using cord blood in an animal model. Kiem recently received a National Institutes of Health RO1 grant to pursue HOXB4 cord-blood expansion studies.
Blood-forming stem cells make all the different cells found in our blood, including immune cells that protect against diseases and platelets that stop bleeding after an injury. Only a very small number of blood cells are this type, but more are found in bone marrow and in cord blood. These stem cells are used to treat blood cancers after chemotherapy or radiation, which kills most blood cells.
Transplants are most likely to succeed when the transplanted stem cells are as similar as possible to the patient's own blood cells. Finding a good match and getting enough of the cells from that source are critical. While cord blood is more readily available than bone marrow and has some "matching" and immunological advantages over bone marrow, it contains only one-tenth the number of stem cells as bone marrow. The fewer the stem cells, the longer it takes a patient to grow a new immune system. Delays can mean death.
Findings on HOXB4
The hope is that the smaller numbers of stem cells found in cord blood or regular blood can somehow be enriched or expanded, thus providing doctors with a much larger pool from which to choose well-matched stem cells. That's where Kiem's research comes into play.
The researchers inserted an active copy of the gene HOXB4 into blood-forming stem cells. Cells with and without the HOXB4 gene were tagged to fluoresce in two different colors so their numbers could be monitored after transplantation.
Early after transplantation in the animal model, the scientists saw a dramatic increase in the HOXB4-treated cells. Six to nine days after transplantation, use of the gene resulted in a 56-fold higher engraftment — the point at which the new blood system forms — compared to the untreated cells. Even six months after transplantation, the gene had a significant, but less pronounced, effect on long-term repopulating cells.
Boosting engraftment process
These findings suggest that HOXB4 might help to expand blood-forming stem cells and speed up the process of engraftment. Given that patients with rapid engraftment have fewer complications, these results are encouraging.
"That early boost is going to be most important for transplantation," Kiem said. "The dramatic expansion could especially help cord-blood transplants."
He noted, however, that this was a small study, and additional studies are necessary before the treatment is considered safe and effective for human clinical trials.
Kiem said an advantage of using the HOXB4 gene is its availability as a recombinant protein. This means it may be possible to expand stem cells directly with HOXB4 protein instead of introducing the HOXB4 gene, and avoid any potential side effects from genetic manipulation of the cells.
The researchers also see the potential for using HOXB4 in gene therapy, which are treatments with the potential to cure inherited diseases. If the scientists are able to expand stem cells with HOXB4 and could screen those cells before infusing them into patients, they could avoid giving the patients any potentially disease-causing cells. "If we could just give good cells — i.e. cells that will not form any malignancies due to vector insertion — that would obviously be the Holy Grail for stem-cell gene therapy," Kiem said.
Co-authors of the paper include two Kiem Lab postdoctoral fellows, Drs. Brian Beard and Xiao-Bing Zhang (lead author), former technician Katherine Beebe, and Dr. Barry Storer, a statistician in the Clinical Research Division. Dr. Keith Humphries, a researcher for the Terry Fox Laboratory at the British Columbia Cancer Agency in Vancouver, also contributed.
Kiem has been collaborating with Humphries, a co-investigator on this study, for several years. Humphries' research focuses on the HOX genes, and he was the first researcher to study the HOXB4 gene in a mouse model.