Role of the cannabinoid receptor CB1 in the regulation of bone marrow hematopoiesis

Shakir, George (2025): Role of the cannabinoid receptor CB1 in the regulation of bone marrow hematopoiesis. Dissertation, LMU München: Medizinische Fakultät

Abstract

Atherosclerosis is the major underlying cause of cardiovascular diseases, which are the leading cause of death worldwide. Endogenous lipid mediator signalling through cannabinoid receptors plays a causal role in atherosclerosis, and blocking the cannabinoid receptor 1 (CB1) has been shown to reduce atherosclerotic plaque burden and improve metabolic risk factors. To date, experimental studies have mainly focused on the effects of CB1 on vascular and myeloid cells in atherosclerosis. However, the role of CB1 signalling in de novo leukocyte production in the bone marrow, a process called hematopoiesis, is still largely unknown. Given that hypercholesterolemia leads to increased monocyte production in the bone marrow and thereby promotes atherosclerotic plaque formation, the aim of this thesis was to study the effect of global loss of CB1 signalling on hematopoiesis. Furthermore, mechanistic experiments were designed to clarify the specific contribution of the hematopoietic versus stromal cell CB1 in this process. Deficiency of the CB1 encoding gene Cnr1 had minimal effect during homeostasis on mature myeloid cells and hematopoietic stem and progenitor cells (HSPCs) during homeostasis. Under low-grade inflammation, achieved by backcrossing with mice on atherogenic apolipoprotein E deficiency (Apoe-/-) background, Cnr1 deficiency increased monocytes in blood and femur, reduced bone marrow stem cell factor (SCF) levels, increased C-X-C motif chemokine receptor 4 (CXCR4) expression on myeloid progenitors, and led to enhanced mobilization of HSPCs into the blood. This phenotype was predominantly observed in male animals, whereas females did not exhibit such a phenotype but rather displayed reduced neuronal innervation in the bone marrow niche. Upon Western diet (WD) feeding, both female and male Cnr1 deficient mice developed monocytosis and larger atherosclerotic plaques compared to the corresponding controls. Besides, Cnr1 deficiency affected the viability of HSPCs. Bone marrow transplantation experiments showed that stromal Cnr1 expression is important for myeloid differentiation during chronic inflammation. In mice lacking Cnr1, G-CSF injection led to an accumulation of common myeloid progenitors, further highlighting the importance of CB1 in acute inflammatory responses. Additionally, an increase in common myeloid progenitors was also observed in Ldlr-/- mice upon peripheral CB1 antagonism. However, this phenotype was only observed in males. Finally, single cell RNA sequencing revealed that Cnr1 deficiency in myeloid progenitors was associated with genes that play a role in apoptosis and oxidative stress, and that these genes are predicted to be regulated by transcription factors linked to myeloid differentiation (such as CEBPB and PU.1). These data highlight a role for CB1 in regulating hematopoiesis during acute and chronic inflammation. More in-depth studies are needed to determine which specific cell types in the Summary 2 hematopoietic niche are primarily regulated by CB1 and the underlying downstream mechanisms.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. Mai 2025
• 1. Bericht­erstatter:in: Marten-Steffens, Sabine