Significant research is ongoing at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. The center’s latest breakthrough was the discovery that a unique protein, pleiotrophin, can promote recovery of bone marrow-derived stem cells and the blood system after injury. The findings may lead to improved curative treatments and procedures for cancer and blood related-diseases. The study was published online in the Journal of Clinical Investigation on September 24.
The study authors explain that hematopoietic stem cells (HSCs), which are the cells that produce red and white blood cells, have been examined to gain understanding the mechanisms whereby the bone marrow microenvironment regulates self-renewal and repair of HSCs. The research conducted by senior author Dr. John Chute, UCLA Professor of Hematology/Oncology and Radiation Oncology, has advanced the theory that bone marrow endothelial cells (the cells that form the lining of blood vessels) play a major role in HSC regeneration. He also suggested that, following injury or stress, the blood system might benefit from and be informed by activities in the bone marrow that direct HSCs to initiate recovery.
The researchers demonstrated that pleiotrophin acts upon HSCs by binding to a receptor on the stem cell and activating a pathway known as the RAS signaling pathway. After an injury, this activation of RAS signaling promotes the recovery of the stem cell and blood system. For the study, the investigators used mouse models to administer pleiotrophin after the rodents had received a lethal dose of radiation. They found that the protein promoted blood stem cell growth and faster blood system recovery. As a result, two thirds of the micel survived. The investigators also added a RAS inhibitor (a substance that binds to the RAS pathway and prevents it from functioning) to the treatment; they found that the inhibitor reversed 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.”
The authors note that, worldwide, millions of cancer patients currently receive some form of chemotherapy or radiation therapy with the goal of curing their disease. Unfortunately, most of them will suffer damage to the blood system as a result. Current treatment methods are cyclical (generally requiring a 30-day wait period between treatments) to allow the blood system time to heal and repair. The researchers are currently working toward a Phase I clinical trial in which patients undergoing bone marrow transplantation and patients receiving chemotherapy would receive pleiotrophin with the goal 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,” explained Dr. Chute.