High-magnification photographs (top row) of the bone marrow of mice 10 days after radiation exposure illustrate that PTN treatment improves the recovery of the blood system and that co-treatment with an inhibitor of the Ras pathway blocks this benefi t. The bottom row demonstrates that irradiated control mice (at left) have depletion of blood stem cells (ckit+sca-1+) at 10 days after radiation exposure, but treatment with PTN accelerates recovery of the blood stem cells.
UCLA scientists have shown how a unique protein in human bone marrow can drive stem cells to repair our blood system after an injury. The discovery offers a roadmap that could lead to more effective radiation and chemotherapy treatments for people with cancer and other blood-related diseases.
Hematopoietic stem cells were a key to the new study. Scientists have long investigated hematopoietic stem cells, which have the ability to become any other type of blood cell, such as red or white blood cells, to try to understand how bone marrow regulates and instructs them to regenerate and repair themselves.
In prior research, John P. Chute, MD, professor of hematology and radiation oncology, discovered that endothelial cells — the cells that make up the lining of blood vessels in our bone marrow — play a key role in telling hematopoietic stem cells how to renew and repair themselves. He theorized that following an injury or another stress to our body, the blood system as a whole benefits, as the activity in bone marrow directly drives the stem cells to promote and accelerate recovery. In the new study, Dr. Chute and colleagues built upon their earlier work to identify a new protein called pleiotrophin (PTN). They discovered that the protein binds to hematopoietic stem cells and that it is this process that activates the blood stem cells to stimulate the recovery of our entire blood system.
Dr. Chute’s team conducted experiments in mouse models to administer PTN after a normally lethal dose of radiation. They found that hematopoietic stem cells and the blood system recovered faster with pleiotrophin than without it, and in two-thirds of the cases the animal survived. Additionally, they found that when they did the opposite — actually blocking PTN and thereby preventing it from functioning — the blood stem cells saw no advantage in recovery. This strongly suggests that the protein is key in accelerating recovery of the blood system.
“We have now discovered the mechanism by which pleiotrophin can instruct blood stem cells to regenerate,” says Dr. Chute, who is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “By modeling it for potential use in human patients, this opens the door for tremendous therapeutic possibilities.”
Dr. Chute and his team are currently pursuing a Phase I clinical trial with the goal of accelerated recovery for patients undergoing all types of radiation and chemotherapy, as well as lessened delays between treatments.
“Pleiotrophin mediates hematopoietic regeneration via activation of RAS,” Journal of Clinical Investigation, September 24, 2014