HSCs are found in small numbers in the bone marrow, the peripheral blood, and in cord blood, which is harvested from the umbilical cord at birth. Cord blood is increasingly being used for transplantation, but the low number of HSCs present in a unit of cord blood means that transplanted cells can be slow to establish themselves (or engraft) in an adult recipient, prolonging the time the patient is susceptible to infections. Consequently, researchers are looking for ways to expand HSCs prior to transplantation. HOXB4 is known to be involved in stem cell maintenance and had shown some promise for stem cell expansion in mice. To investigate the potential of HOXB4 treatment for HSC expansion before transplantation in humans, Kiem and colleagues therefore turned to nonhuman primates, an established preclinical model for HSC transplantation and gene therapy.
The team showed that HOXB4 over-expression in populations of cells enriched for stem cells (i.e. those that are used for transplantation) for 6-9 days prior to transplantation greatly improved their subsequent engraftment in monkeys whose hematopoietic system had been destroyed through radiation. These results suggest that HOXB4-mediated expansion of stem cells could accelerate the engraftment of HSCs from sources that contain limited numbers of stem cells, such as cord blood. This was a proof-of-principle study that used small numbers of monkeys. Given the encouraging results, additional experiments are now planned to further test whether HOXB4 can eventually be used to improve the expansion and engraftment of stem cells in patients whose hematopoietic system has failed.
Kiem and colleagues achieved HOXB4 overexpression through introducing an active copy of the gene into the cells. However, because HOXB4 protein is available in recombinant form (i.e. produced in cell culture, much like human insulin), it should be possible to treat HSCs directly with the protein, avoiding the potential problems associated with genetic manipulation of the cells. As the reviewers of the article commented, such "clean expansion" of HSCs holds great potential for application in human transplant recipients.
Citation: Zhang XB, Beard BC, Beebe K, Storer B, Humphries RK, et al. (2006) Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells. PLoS Med 3(5).
PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030173
PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-03-05-kiem.pdf
PRESS-ONLY PREVIEW OF THE SYNOPSIS: http://www.plos.org/press/plme-03-05-kiem-syn.pdf
Hans Peter Kiem
Fred Hutchinson Cancer Research Center
Clinical Research Division
+1 206-667-6124 (fax)
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