Our hematopoietic stem cells (HSCs) are responsible for the production of a staggering 600 billion cells per day within the bone marrow, where they integrate proliferative signals from their own progeny, bone-forming cells, mesenchymal stromal cells, Schwann cells and specialized sinusoidal vasculature. Adipocytes, although long ignored due to their scarcity in mouse models in homeostatic conditions, constitute the most abundant cell type within the adult human bone marrow, with a yet unclear role on systemic and local metabolism.
We have found that preventing the formation of mature marrow adipocytes, which increase throughout the skeleton with high-fat diet or upon chemo- or radiotherapy, induces HSC quiescence. Conversely, preventing adipocytic differentiation, genetically or pharmacologically, accelerates hematopoietic recovery. I will discuss how a search for clinically relevant compounds that could modulate marrow adipogenesis has led us to the discovery of NAD boosting strategies as regulators of HSC fate through increased mitochondrial recycling, with potentially important translational implications for the care of patients with bone marrow failure or undergoing intensive chemotherapy.