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Scientists from UCLA's Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have shown for the first time how the novel protein pleiotrophin can drive recovery of bone marrow-derived stem cells and the blood system after injury. These groundbreaking findings provide a roadmap for more curative future therapies and overall improved treatment protocols for blood-related cancers and diseases.
Led by Dr. John Chute, senior author and UCLA Professor of Hematology/Oncology and Radiation Oncology, the study was published online ahead of print in theJournal of Clinical Investigation on September 24, 2014.
Hematopoietic stem cells (HSC, the cells that produce the blood and immune system) have been used in the laboratory to study the mechanisms through which the bone marrow microenvironment regulates HSC self-renewal and repair. Dr. Chute's research has contributed conceptually to the idea that bone marrow endothelial cells (the cells that form the lining of blood vessels) play an instructive role in HSC regeneration. He further theorized that following injury or stress, the blood system as a whole benefits and is informed by activities in the bone marrow vasculature that direct HSCs to initiate recovery.
Building upon this research, Dr. Chute and colleagues demonstrated that pleiotrophin, a protein secreted by the so-called stem cell vascular niche, acts upon HSCs by binding to a receptor on the stem cell and activating a pathway called the RAS signaling pathway. Following injury, this activation of RAS signaling is what drives the recovery of the stem cell and blood system.
Dr. Chute's team utilized mouse models to administer pleiotrophin after a lethal dose of radiation. Results showed that the blood stem cells and blood system recovered faster, and in two thirds of the cases the animal survived. In tandem, Dr. Chute's team also used a RAS inhibitor (that binds to the RAS pathway and prevents it from functioning), and found that the inhibitor took away the survival advantage completely.
"We have now discovered at least one of the mechanisms through which a blood vessel-derived protein instructs blood stem cells to regenerate, and this has been shown both in vitro and in vivo," said Dr. Chute. "By modeling it for potential use in human patients, this opens the door for therapeutic possibilities."
Millions of cancer patients worldwide currently receive some form of chemotherapy or radiation therapy in hopes of curing the disease, and most will suffer damage to the blood system as a result. Current therapeutic protocols are cyclical (generally requiring a 30-day wait period between treatments) to allow the blood system time to heal and repair.
Dr. Chute and his team are currently working toward a Phase I clinical trial in which patients undergoing bone marrow transplantation and patients receiving damaging chemotherapy would receive pleiotrophin with the objective of accelerating the recovery of the blood system.
"With this discovery, we hope to provide the basis for improving outcomes for patients with cancer or other blood-related diseases and who are undergoing highly toxic treatments," said Dr. Chute.
This research was supported by funding from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. Additional funding was provided by the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the Jonsson Comprehensive Cancer Center through philanthropy and other sources.
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| About the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Comprehensive Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.
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