Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1+ precursors and postnatally from bone marrow–derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche

The Origin and Maintenance of Resident Aortic Macrophages

Macrophages maintain tissues homeostasis, while also contributing to numerous pathological processes, making them attractive targets for therapeutic intervention. Therapeutic design however, requires detailed understanding of macrophage origins, the mechanisms that maintain them, and their functional attributes in tissue- and disease-specific contexts. The origin and maintenance of vascular macrophages in the steady state and inflammation has yet to be elucidated. In the following thesis we establish that the murine aorta contains macrophages derived from embryonic and definitive hematopoietic precursors. We demonstrate that aortic macrophages are maintained locally and are able to replenish following inflammation via proliferation. Microarray analysis revealed two important traits: aortic macrophages are distinct from other tissue resident macrophages and following inflammation aortic macrophages rapidly return to homeostasis. In addition, we identify the CX3CR1-CX3CL1 axis as important for aortic macrophage survival. Taken together, this thesis provides a basis upon which future studies of aortic macrophages may be undertaken.M.Sc.2017-11-24 00:00:0

c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells

Summary: Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease. : Shikatani et al. demonstrate that the nuclear transcription factor c-Myb exacerbates experimental atherosclerosis directly through its effects on B lymphocytes. Paradoxically, c-Myb promotes B2 cell development yet limits numbers of IgM-producing antibody-secreting cells and levels of atheroprotective OxLDL-specific IgM antibodies

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma