Endokannabinoidler ve Reseptörlerinin İnsan Hematopoetik Kök Hücreleri ve Kemik İliği Kaynaklı Mezenkimal Kök Hücrelerindeki Varlığı ve Düzeyinin Araştırılması

Abstract

Köse, S. The Effects of Endocannabinoids and Their Receptors on Human Bone Marrow Mesenchymal and Hematopetic Stem Cells. Hacettepe University Institude of Health Sciences, Ph.D. Thesis in Stem Cell Science, Ankara, 2017. Lipid-structured endocanabinoids are endogenous morphine ligands and present widespread receptor-mediated effects at physiological and pathological levels on the central and peripheral nervous system as well as many other systems. These effects are partially realized through mechanisms affecting cell growth, differentiation, apoptosis and migration at the molecular level. The bone marrow microenvironment consists of hematopoietic stem cells (HSCs), fibroblasts, adipocytes, endothelial cells, osteoblasts and widespread presence of mesenchymal stem cells (MSCs). The endocannabinoid system also takes part in mobilization of the HSCs through cytokines. Although it is known that the endocannabinoid system plays a role in cytokine-mediated hematopoietic stem cell migration, the effects of these mediators on Granulocyte-Colony Stimulating Factor (G-CSF) stimulated and unstimulated human bone marrow derived HSC mobilization have never been compared and their relationship with the sympathetic nervous system is currently unknown. During clinical G-CSF mobilization, endocannabinoids and the sympathetic nervous system may be working together. The aim of this thesis is to investigate the receptor mediated effects (proliferation, maturation and migration) of endocannabinoids (AEA, 2AG) on HSCs through MSCs associated beta adrenergic stimulation in GCSF treated or untreated bone marrow samples. The second aim of thesis is determined, applying the cannabinoid agonist/antagonists and/or beta adrenergic receptor agonist/antagonists which is effective on bone marrow microenvironment, arranged whether a dose-dependent interaction between the human HSCs and MSCs. With these purposes results from this study will provide fundamental data for treatment protocols using HSCs and MSCs, which are used in the clinics with the purpose to treat wound healing and immune suppression in various diseases, in concert with endocannabinoids and related metabolic diseases.