Improving Blood Stem Cell Transplantation
A recent study conducted in mice, baboons, and human volunteers has shown that a non-steroidal anti-inflammatory drug approved by the U.S. Food and Drug Administration (FDA), called meloxicam, significantly increased the number of blood (hematopoietic) stem cells (HSCs) and their descendent hematopoietic progenitor cells (HPCs) entering the circulation from the bone marrow, where they typically reside until needed. This finding sheds light on how the body responds to injury and has implications for blood cell transplantation. The hematopoietic niche of the bone marrow supports the survival and self-renewal of HSCs and HPCs, yet prevents the ill-timed release of these cells into the circulation. When used to treat cancers such as non-Hodgkin’s lymphoma and multiple myeloma, high-dose chemotherapy also destroys normal cells such as the HSCs and HPCs in the bone marrow. To replenish the lost cells, HSCs and HPCs are routinely harvested from a donor’s or patient’s blood, and then transplanted back into the patient at the conclusion of the chemotherapy procedure to repopulate the bone marrow. The levels of HSCs and HPCs normally found in blood are very low, and strategies have been devised to mobilize HSCs and progenitor cells out of the bone marrow and into the circulation. The naturally occurring protein G-CSF often is used clinically to mobilize cells, but this strategy does not work for approximately 10 to 20 percent of individuals. Research continues in order to identify more effective strategies to mobilize cells out of the microenvironment of the marrow and into the circulation.
Building on their previous research findings, which showed that prostaglandin E2 enhanced HSC survival and homing to the bone marrow, researchers demonstrated that meloxicam treatment of mice greatly increased the numbers HSCs and HPCs in the circulation. Mice treated with a combination of G-CSF and meloxicam mobilized significantly more cells than those treated with either drug separately. Similar to indings in mice, meloxicam treatment of both baboons and healthy human volunteers increased HSCs and HPCs in the circulation. Additional experiments were conducted to determine how meloxicam exerts its biological effect. Previous research showed that prostaglandin E2 signals through one or more of the four E-prostanoid (EP1-4) receptors. Using genetically altered mouse strains each lacking one of the EP receptors, it was shown that mice lacking EP4 receptor had increased HSCs and HPCs in the circulation and meloxicam had no additional effect. These findings strongly suggest that meloxicam targets the prostaglandin E2/EP4 receptor signaling pathway.
Moreover, the researchers showed that mice deficient in osteopontin, a component of the HSC niche, mobilized HPCs but not HSCs when treated with meloxicam. This result demonstrates that meloxicam decreases osteopontin levels in the HSC niche, which then permits HSC, but not HPC, mobilization out of the marrow.
This study has several potentially important clinical implications. Meloxicam in combination with G-CSF may improve the success rates of blood stem cell transplantation by making it easier to obtain sufficient numbers of cells for transplant. Meloxicam is FDA-approved for use and therefore additional toxicology studies need not be conducted, saving both time and money. And, meloxicam has comparatively few side effects compared to other non-steroidal anti-inflammatory drugs.