Major milestone in the culturing of human blood stem cells

Patients with leukemia, certain autoimmune diseases and genetic defects such as sickle-cell anemia can be treated with blood stem cells either from a donor's bone marrow or from cord blood - but the supply of effective stem cells often runs short.

Now, researchers in the lab of Whitehead Member Harvey Lodish have found a way to multiply in culture adult hematopoietic (blood- forming) stem cells from human cord blood 20-fold, a major milestone that offers promise for bone marrow transplants and perhaps even gene therapy. Cord blood can be easily collected and stored as a frozen product, making it readily available.

“Human cord blood is a rich source of stem cells, but offers too few of those cells to transplant into an adult,” says Lodish. “Previously we identified five growth factors that acting together in culture expanded mouse bone marrow hematopoietic stem cells 30-fold. Building on this research we've now identified five growth factors needed to stimulate human cord blood stem cells to divide in culture and make 20-fold as many stem cells.” The paper was pre-published online in Blood on January 17, 2008.

Two novel growth factors (angiopoietin-like 5 and IGFBP2) work in combination with three previously identified growth hormones (SCF (Stem Cell Factor), TPO (Thrombopoietin) and Flt3 ligand to stimulate the growth of these stem cells.

Known as hematopoietic stem cells, the cells give rise to oxygen-carrying red blood cells, white blood cells, and all of the cells that comprise the immune system. Previous efforts to grow human hematopoietic stem cells in culture have proven extraordinarily difficult because they rapidly differentiate into mature blood or immune cells.

“Our finding builds on previous work studying hematopoietic cells in which we discovered a novel cell population that when cultured in a dish with stem cells enabled them to multiply,” says Chengcheng Zhang, first author of the paper, formerly a postdoctoral researcher in the Lodish lab and now an assistant professor of physiology and developmental biology at the University of Texas Southwestern Medical Center in Dallas. “We searched for genes that were active in these and other stem cell supportive cells, and identified genes that encoded growth factors. We then added the growth factors to the isolated hematopoietic stem cells and increased the number of stem cells in culture.”

To make sure that these were still viable stem cells, the researchers transplanted them into immune-deficient mice, and measured the resulting population of various sorts of human blood and immune system cells successfully growing in the mice.

The researchers note that this finding may also lead to advances in gene therapy, in which a genetic defect would be corrected by administering a healthy version of the gene into a patient. During gene therapy, hematopoietic stem cells from a patient would be isolated and exposed to a harmless virus that expresses a correct version of the mutated gene, and then the stem cells would be transferred back into the patient.

“If we could first culture stem cells such that they divide and make more stem cells before they are reintroduced into the patient, assays could be used to determine if the virus had landed in any undesirable places, in order to ensure that the healthy version of the gene is administered to the patient,” says Lodish. “With a technique such as this, it may be possible to ensure that the gene is inserted into the genome in the correct place.”

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