Granulocyte colony-stimulating factor alters the systemic metabolomic profile in healthy donors

Abstract

IntroductionPeripheral blood stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) from healthy donors are commonly used for allogeneic stem cell transplantation. The effect of G-CSF administration on global serum metabolite profiles has not been investigated before.ObjectivesThis study aims to examine the systemic metabolomic profiles prior to and following administration of G-CSF in healthy adults.MethodsBlood samples were collected from 15 healthy stem cell donors prior to and after administration of G-CSF 10 µg/kg/day for 4 days. Using a non-targeted metabolomics approach, metabolite levels in serum were determined using ultrahigh performance liquid chromatography-tandem mass spectrometry and gas chromatography/mass spectrometry.ResultsComparison of the metabolite profiles of donors before and after G-CSF treatment revealed 239 metabolites that were significantly altered. The major changes of the metabolite profiles following G-CSF administration included alteration of several fatty acids, including increased levels of several medium and long-chain fatty acids, as well as polyunsaturated fatty acids; while there were lower levels of other lipid metabolites such as phospholipids, lysolipids, sphingolipids. Furthermore, there were significantly lower levels of several amino acids and/or their metabolites, including several amino acids with known immunoregulatory functions (methionine, tryptophan, valine). Lastly, the levels of several nucleotides and nucleotide metabolites (guanosine, adenosine, inosine) were also decreased after G-CSF administration, while methylated products were increased. Some of these altered products/metabolites may potentially have angioregulatory effects whereas others may suggest altered intracellular epigenetic regulation.ConclusionOur results show that G-CSF treatment alters biochemical serum profiles, in particular amino acid, lipid and nucleotide metabolism. Additional studies are needed to further evaluate the relevance of these changes in healthy donors.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-016-1139-x) contains supplementary material, which is available to authorized users.

Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients

“…Even in treated HSC donors, G-CSF plasma levels ranged around 1 ng/ml. Other studies have described slightly higher plasma concentrations ranging from 4 to > 15 ng/ml ( 35 ). In our in vitro experiments with purified neutrophils, 10 ng/ml G-CSF had no effect on neutrophil chemotaxis, only 50 ng/ml G-CSF impacted neutrophil chemotaxis.…”

“…Instead of harvesting bone marrow surgically from the pelvis bone, which requires, e.g., general anesthesia, the cells of interest are collected from the peripheral blood. Yet again, there is growing evidence that G-CSF treatment alters more physiological functions than the blood cell count ( 22 , 35 ). Our study analyzed key neutrophil functions, i.e., chemotaxis, ROS production, and phagocytosis, in isolated neutrophils from the peripheral blood of HSC donors and allogeneic transplant recipients by using well-established in vitro stimuli and assays.…”

“…Our study analyzed key neutrophil functions, i.e., chemotaxis, ROS production, and phagocytosis, in isolated neutrophils from the peripheral blood of HSC donors and allogeneic transplant recipients by using well-established in vitro stimuli and assays. The individuals included in our study received standard dosages of G-CSF (10 μg/kg/d) and the resulting plasma concentrations were in the expected ranges ( 34 , 35 ). As expected, G-CSF treatment substantially increased the number of neutrophils in the circulation.…”

Immunological heterogeneity of healthy peripheral blood stem cell donors – preharvesting donor characteristics, additional heterogeneity induced by granulocyte colony-stimulating factor and possible importance for outcome after allotransplantation

“…Several metabolites have immunoregulatory functions, and G-CSF mobilization in healthy donors alters energy, amino acid, carbohydrate, lipid, nucleotide, and vitamin metabolism; most of these effects are common but exceptional donors are seen [9].…”

Immunological Heterogeneity of Healthy Peripheral Blood Stem Cell Donors—Effects of Granulocyte Colony-Stimulating Factor on Inflammatory Responses

“…However, the effects of G-CSF therapy in healthy individuals are complex as illustrated both by the frequent reversible side effects (e.g., musculoskeletal pain) and uncommon but more severe toxicity (e.g., splenic rupture and pulmonary toxicity), including progression of arthritis as an example of a proinflammatory effect [ 11 , 12 ]. A recent study also described metabolic effects of G-CSF therapy in healthy stem cell donors, and these effects may influence immunoregulation [ 13 ]. Furthermore, the systemic level of the proinflammatory acute phase stimulant interleukin-6 (IL-6) is also increased for a subset of such donors [ 9 ], but it is not known which cells are responsible for this IL-6 response [ 6 , 14 ].…”