Bone marrow (BM) constitutes one of the largest organs in mice and humans, continuously generating, in a highly regulated manner, red blood cells, platelets, and white blood cells that together form the majority of cells of the body. In this review, we provide a quantitative overview of BM cellular composition, we summarize emerging knowledge on its structural organization and cellular niches, and we argue for the need of multidimensional approaches such as recently developed imaging techniques to uncover the complex spatial logic that underlies BM function in health and disease.Since Neumann and Bizzozero independently proposed in 1868 that the origin of blood cells was to be found in soft tissues contained inside bone cavities, the bone marrow (BM) has continued to fascinate scientists and clinicians alike. 1,2 Yet more than a century later, our understanding of how the hematopoietic, immune, and bone-forming tasks of the BM are tightly controlled and integrated in the context of one common anatomical space is still incomplete.
Methodological approaches and advances to study BM tissuesEarly studies on BM cellular composition and microarchitecture date back to the 19th century when the first biopsies of marrow content were performed in living individuals. 3 Microscopic observation of BM smears and examination of histological sections became the standard technique, which is still used to this day to study, diagnose, and classify hematologic disorders. The realization in the post-World War II era that transplantation of BM cells from healthy individuals could rescue the lethal effects of high-dose irradiation on hematopoiesis galvanized scientific interest in BM and lead to the development of methods to detect and measure hematopoietic stem and progenitor cell (HSPC) activity, absolute cellularity, lineage-specific half-lives, and kinetics of cell production in the BM of humans and in laboratory animals. 4,5 Gradual improvements in light and electron microscopy further refined the understanding of the quantitative composition and ultrastructural features of BM tissues. 6 The biggest leap in the fields of immunology and hematology came with the advent of recombinant antibody technology and flow cytometry in the 1960s. These breakthroughs permitted the identification, quantification, and isolation of diverse populations from highly heterogeneous cell suspensions through detection of phenotypic traits. 5 Indeed, to this day, flow cytometry remains the technological mainstay for the study and dissection of the hematopoietic system.Immunolabeling methods were further adopted in modern fluorescence-based microscopy to discriminate cellular phenotypes in tissue sections and study cellular organization in the BM. In recent years, confocal microscopy has become the most popular modality to define spatial relationships and study developmental-stage specific localization patterns, with a keen interest of many groups in the dissection of HSPC niches. 7 In addition, intravital multiphoton microscopy is employed to obtain dyna...
