Adult skull bone marrow is an expanding and resilient hematopoietic reservoir
The bone marrow microenvironment is a critical regulator of hematopoietic stem cell self-renewal and fate. While it is appreciated that aging, chronic inflammation and other insults compromise bone marrow function and thereby negatively affect hematopoiesis, it is not known whether different bone compartments exhibit distinct microenvironmental properties and functional resilience. Here, we have employed imaging, pharmacological approaches, and mouse genetics to uncover specialized and highly surprising properties of bone marrow in adult and aging skull. Specifically, we show that the skull bone marrow undergoes lifelong expansion involving vascular growth, which results in an increasing contribution to total hematopoietic output. Furthermore, skull is largely protected against major hallmarks of aging, including upregulation of pro-inflammatory cytokines, adipogenesis and loss of vascular integrity. Striking dynamic and rapid changes to the skull vasculature and bone marrow are induced by physiological alterations, namely pregnancy, but also pathological challenges, such as stroke and experimental chronic myeloid leukemia. These responses are highly distinct from femur, the most extensively studied bone marrow compartment. We propose that skull harbors a protected and dynamically expanding bone marrow microenvironment, which is relevant for experimental studies but, potentially, also clinical treatments in humans. Overall design: FACS-sorted hematopoietic stem and progenitor cells (HSPCs) and MACS hematopoietic lineage-depleted stromal cells from skull or femoral bone marrow of young or old mice analyzed using scRNA-seq UPDATE: [June-12-2025] The titles of GSM8472477 and GSM8472478 were updated ("HSPC" to "Haem").