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Stem cell expansion and more

02.05.2006

More stem cells are better - expanding hematopoietic stem cells with HOXB4

Transplantation of hematopoietic stem cells (HSCs, the cells that can give rise to all blood and most immune cell types) can save patients whose own hematopoietic system is defective or has been destroyed (often through radiation or chemotherapy of cancer). HSCs are very rare, and it is often hard to obtain enough of them for a successful transplant.

To overcome this limitation, Hans-Peter Kiem and colleagues have developed a way to expand HSCs in the laboratory prior to transplantation. As they report in the international open-access journal PLoS Medicine, expression of a gene called HOXB4 can instruct stem cells to divide and make more stem cells. When the researchers tested those expanded cell populations in monkeys that had received a lethal dose of radiation, they found that they were better at reconstituting the monkeys’ immune and blood systems.

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).

CONTACT:
Hans Peter Kiem
Fred Hutchinson Cancer Research Center
Clinical Research Division
Seattle, USA
+1 206-667-4425
+1 206-667-6124 (fax)
E-mail: hkiem@fhcrc.org

Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype

In a study done in West Africa, Dr. Sarah Atkinson and colleagues from the London School of Hygiene and Tropical Medicine in London showed an association between a particular type of haptoglobin (Hp2-2) and anemia in children, in an area where malaria is very common. Haptoglobin is a protein that picks up the free hemoglobin which is released after red cells are damaged by malaria. This increased occurrence of anemia in these children may be because the particular type of haptoglobin, Hp2-2, is less able pick up the hemoglobin released from red cells. One suggested explanation of why this genetic variant remains in the population despite being associated with anemia is that it may provide protection from life-threatening malaria. In a related perspective, Stephen Rogerson from the Royal Melbourne Hospital discusses further the implications of the study.

Citation: Atkinson SH, Rockett K, Sirugo G, Bejon PA, Fulford A, et al (2006) Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype. PLoS Med 3(5): e172.

CONTACT:
Sarah Atkinson
London School of Hygiene and Tropical Medicine
Nutrition and Public Health Intervention Unit
Keppel Street
London WC1E 7HT, United Kingdom
+44 (0)2079588140
+44 (0)2079588111 (fax)
satkinson@kilifi.mimcom.net

Related PLoS Medicine Perspective article:

Citation: Rogerson S (2006) What is the relationship between haptoglobin, malaria, and anaemia? PLoS Med 3(5): e200.

CONTACT:
Stephen Rogerson
Royal Melbourne Hospital
Parkville, Victoria 3052, Australia
+61 3 8344 3259
sroger@unimelb.edu.au