GRANÜLOSİT KOLONİ UYARICI FAKTÖRÜN HÜCRE MOBİLİZASYONUNDAKİ ROLÜNÜ, LİPOLİTİK ETKİSİNİ AYDINLATMAK İÇİN KEMİK İLİĞİNDE METABOLOM VE ADAY BİR ENZİM OLARAK FOSFOLİPAZ C BETA 2 DEĞERLENDİRMESİ

Abstract

Granulocyte Colony Stimulating Factor (G-CSF) is a mobilizing factor of hematopoietic stem cells (HSC). Protein and lipid metabolism have important roles in HSC mobilization. The proteases, membrane lipid clusters and the Phospholipase C (PLC) enzyme have important roles in G-CSF-mediated mobilization. However, there are no sufficient studies about the effect of lipid metabolism on mobilization. In our study, we examined the bone marrow plasma samples of 30 healthy individuals who were donors for HSC transplantation. Metabolomic-lipidomic analyses and PLC enzyme activity analysis were performed on samples from individuals with (2 or 3 days) and without in vivo G-CSF exposure before HSC collection. In the results of metabolomics analysis; 3-hydroxypropanoic acid, fucose, glutamic acid, O-phospho-L-Serine, phosphoric acid, ribitol, trimethyllysine, myo-inositol, oxaloacetic acid metabolites are significantly increased; alpha-glucosamine 1-phosphate, proline and threonine metabolites are significantly decreased with G-CSF exposure. The change in fucosylation metabolism, characterized by an increase in fucose values, was thought to indicate the suppression of adhesion and stimulation of mobilization in the bone marrow niche, while the decrease in essential amino acid levels was associated with increased cell proliferation and increased protein demand as a result of G-CSF exposure. In lipidomic analysis, the most remarkable changes are on ether-linked phosphatidylcholines (such as plasmalogens). Phosphatidylcholines and ether-linked phosphatidylcholines are important components of cell membranes and lipid rafts. The metabolic change observed in lipid rafts as a result of G-CSF exposure suggest to reflect the G-CSF-related immunoregulatory and inflammatory response. Although there is no significant difference in PLC analysis; there was a decrease in mean values after G-CSF exposure. On the other hand, the increase in myo-inositol and phosphoric acid metabolites may indicate a decrease in glycosylphosphatidylinositol (GPI) anchor formation after G-CSF exposure. The switched metabolites were shown to be in energy-related, amino acid-related and lipid-related pathways by enrichment analysis. In conclusion, our study showed that there were significant variations mainly in energy, amino acid and lipid metabolism after G-CSF exposure. Our findings support that G-CSF contributes to mobilization through various mechanisms, including lipid metabolism. As far as is known, metabolic changes in the bone marrow niche where G-CSF exerts its direct effect have not been investigated before. In this respect, the data obtained in our study is unique and will contribute to the development of bone marrow-targeting treatments that will affect healthy and pathological hematopoiesis.