23/04/10

“Perhaps more importantly, systemic treatment with pleiotrophin may have the potential to accelerate recovery of the blood and immune system in patients undergoing chemotherapy or radiotherapy,” Chute said in a press release.Growth factors—usually a protein or steroid hormone—serve as one way that cells send signals to each other. In blood, HSCs are naturally surrounded by growth factors that provide a supportive environment for growth and self-renewal. But since researchers don’t fully understand which proteins signal the cells to self renew and how they do it, they are reluctant to use cultured HSCs in patients. Chute and his team wanted to find a soluble growth factor that could be added to cultures to produce cells that can be safely transplanted.

Prior research has shown that HSCs grow well when cocultured with primary human brain endothelial cells (HUBECs), so the team suspected that HUBECs might produce proteins that support the undifferentiated self-renewal of HSCs. After comparing the HUBEC genome with that of non-brain human endothelial cells—which don’t support HSCs growth well—the team located 13 growth factor genes with expression levels five times higher in the HUBECs. Specifically, they found that the gene for pleiotrophin was expressed about 25 times more in HUBECs than in other endothelial cells. Next, they checked to see if bone marrow progenitor cells had pleiotrophin receptors using an antibody specific to the protein. They found that about 89% of the cells had a receptor.

For the next stage of the experiment, Chute’s team cultured mouse bone marrow HSCs for 14 days. Cultures with growth factors and pleiotrophin were compared with a control group of just growth factors. The researchers found that the cells with pleiotrophin did twice as well as those in the control group. Transplants of these pleiotropin-treated cells were introduced into mice with irradiated bone marrow; wherein the team discovered that the transplants successfully regenerated the destroyed bone marrow in the mice as early as 4 weeks post-transplant and at 10 times the rate of untreated mice.

Chute said that it will be important to do more animal studies before testing the method in humans. “At this point, any progress we can make that helps us better understand which biological pathways are activated in stem cells in response to pleiotrophin will help move the discovery forward,” said Chute.

The paper “Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells” was published in Nature Medicine online ahead of print on Mar. 21.