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Successful transplantation of hematopoietic stem cells (HSCs) requires both the homing and engraftment of stem cells to the bone marrow, two processes that may not be very efficient and force a need for large numbers of HSCs for transplantation. To date, is has been unclear whether these processes can be artificially enhanced. Now, a study in the August 13 Science reveals that the inhibition or genetic deletion of the peptidase CD26 on donor stem cells increases transplantation efficiency, a result that suggests this method may prove useful for the clinical improvement of bone marrow transplants. The research grew out of over a decade of study on the clinical use of umbilical cord blood as a source of HSCs, according to senior author Hal Broxmeyer, from the Indiana University School of Medicine and senior author of the Science study. Broxmeyer was part of the original research team that first used cord blood as a source of hematopoietic stem cells for transplantation in 1989. Because cord blood has a limited number of stem cells, its use has largely been restricted to children. "My big concern was how to deal with this, since, if you could figure out a way to use these stem cells in adults, it would really broaden their applicability," Broxmeyer told The Scientist. Broxmeyer's laboratory, as well as others, had initially explored that idea of expanding the population of stem cells in cord blood under ex vivo conditions. "But to date, the results of these studies are not that encouraging," he said. "This doesn't mean its not going work some day, but right now, we figured there had to be another way."A clue to a way to expand stem cells came from the observation that the molecule CXCL12, which is though to be involved in the homing of stem cells, was a target of CD26's peptidase activity. Broxmeyer, lead author Kent Christopherson, and their colleagues reasoned that the CD26 inhibition might therefore increase stem cell homing and engraftment, and together they set out to investigate this in mice.Upon treating mice bone marrow HSCs for 15 minutes with a CD26 inhibitor (Diprotin A), the researchers measured a nine-fold increase in homing efficiency. Similarly, cells in which CD26 had been deleted (CD26-/-) showed a 11-fold increase. The treatment of low-density bone marrow donor cells, which more accurately resemble stem cells used in a clinical setting, also increased homing efficiency. Furthermore, CD26-/- cells made a more significant contribution to long-term donor HSCs engraftment in lethally irradiated mice, with fewer CD26-/- HSCs being required for mouse survival compared with normal HSCs. "I think these results are going to be very useful, since it appears [Broxmeyer and colleagues] have come up with a very simple strategy for possibly enhancing engraftment," said David Scadden from Harvard Medical School, who was not involved in the Science study. "This could enable the use of cord blood and may reduce the complexity of harvesting bone marrow from donors." Yair Gazitt, from the University of Texas, San Antonio, also felt the research was an important contribution. "This article is very important in the basic understanding of the mechanism of mobilization of HSCs, in particular, the involvement of proteases in the process," Gazitt, who was not involved in the Science study, told The Scientist.Gazitt, Scadden, and Broxmeyer all cautioned that the research has only presently been completed in mice. "The big thing is whether this is going to hold up with human cells in a clinical study, and that is what we are working on now," said Broxmeyer.Nevertheless, all three researchers envision the possibility that the inhibition of CD26, or similar molecules, may enhance clinical HSC transplants in the future. "The easiest way to utilize this approach clinically is by the use of small molecule inhibitors," said Gazitt.In the end, it all comes down to where the need is for improved transplantation efficiency, said Scadden, adding that "[Broxmeyer and colleagues] highlight the expanded use of umbilical cord blood, and that is the real opportunity."

Enhancing stem cell transplants

Inhibition of peptidase CD26 found to increase efficiency of procedure in mice

Aug 12, 2004

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