Mechanism Identified for Adverse Events Caused by Stem Cell Harvesting

The mechanism for adverse events (AEs) of G-CSF —–widely used for peripheral blood hematopoietic stem cell harvesting (PBSCH)–– was identified in a new study published in Blood. A new function of neutrophils was also found.

G-CSF is a method that stimulates the bone marrow in order to mobilize stem cells in the peripheral blood.

Although this method is widely used for PBSCH, the mechanism for the mobilization of hematopoietic cells by G-CSF was previously unclear. Furthermore, there were no convincing reasons that explained the existence of “poor mobilizers,” and the mechanism of unfavorable AEs caused by G-CSF, such as bone pain and fever.

For the study, researchers focused on the efficacy of standard anti-inflammatory medications for the treatment of fever and bone pain caused by G-CSF.

Since these anti-inflammatory drugs suppress PGE2 production, which is involved in inflammation and pain, researchers hypothesized that PGE2 may be the cause of AEs by G-CSF.

The results of the study using mouse models showed that PGE2 inhibited the mobilization of hematopoietic stem cells in peripheral blood, and blood cells produced PGE2 by the treatment of G-CSF.

Additional results revealed that among the blood cells, neutrophils produced PGE2 by G-CSF-induced stress stimulation (sympathetic nerve stimulation).

The fever response was investigated in denervated mice by neurotoxin and neutrophil-depleted mice by antibodies, resulting in G-CSF-induced fever being diminished in the mice. Furthermore, PGE2 affected osteoblastic cells in the bone marrow to increase osteopontin (OPN). This is a known inhibiting factor of stem cell mobilization to peripheral blood, which results in a decrease in the number of mobilized stem cells.

The findings revealed that the production of PGE2 by neutrophils governed by the sympathetic nervous system is behind the mechanism for AEs caused by G-CSF, and is one of the causes of suppression of stem cell mobilization, according to the study.

The authors noted that the study results provides information to treat AEs of G-CSF, as well as the ability to predict the currently unpredictable poor mobilizers, and treat them with OPN antibodies.