The impact of dyslipidemia on hematopoiesis in the skull

Dyslipidemia is the key driver of atherosclerosis that underlies myocardial infarction (heart attacks) and many strokes, the leading causes of death worldwide. One of the hallmark features of atherosclerosis is the robust accumulation of inflammatory white blood cells in the arterial wall. The production of these immune cells takes place in specialized niches of the bone marrow via a process called hematopoiesis. Heightened hematopoiesis in long bones, such as the femur and tibia is extensively documented in atherosclerosis and contributes to disease progression. However, it remains unknown whether distinct bone compartments at various anatomical locations exhibit different responses to dyslipidemia. In this project, we will elucidate whether and how hypercholesterolemia affects local hematopoiesis in the central nervous system (CNS), namely in the bone marrow of the skull. It has been increasingly evident that the immune system operates as a guardian of the CNS in supporting brain function. The skull bone marrow has emerged as an important reservoir of immune cells, and therefore, immune responses mounted in the skull have a crucial role in protecting the CNS upon infections or sterile inflammation. Moreover, both in mice and humans, the skull bone marrow gradually expands over the lifespan while withstanding multiple characteristics of ageing, thus raising considerations for its role in peripheral white blood cell supply. Importantly, no negative regulators of skull bone marrow hematopoiesis have been identified so far. Preliminary observations included in this project demonstrate for the first time that cholesterol-rich diet impacts the hematopoietic output of the skull bone marrow in atherosclerosis-prone mice. Altered responsiveness of the skull bone marrow upon hypercholesterolemia may have critical and wide-spanning relevance for multiple diseases concerning both the CNS (stroke and Alzheimers disease) as well as peripheral atherosclerosis. This research is a significant joint effort by a team of world-renowned scientists and doctors who will apply state-of-the-art techniques and methodologies to identify the biological pathways by which hypercholesterolemia impacts the skull bone marrow and study its long-lasting consequences. Further, we aim to translate the findings of this project and test the relationship between dyslipidemia and skull BM expansion in humans. We expect to identify novel candidate molecules as potential therapeutic targets for restoring adequate hematopoiesis in the skull. Last, we will use our data to inform public health policy and advocate for appropriate diet as a critical component of a healthy lifestyle.