The bone marrow is an important site for the interrelated processes of hematopoiesis granulopoiesis erythropoiesis and lymphopoiesis. marrow (BM) is a critical site of immune cell development erythropoiesis and provides a niche for plasma cells and memory T cells. While the cell populations ABT-737 and structural elements in the BM are typically characterized by composition and morphology (1 2 the application of novel imaging technologies such as intravital imaging and laser scanning cytometry has allowed the field to better define the microenvironments within this complex organ. Similarly the use of conditional knock out technologies has helped to clarify the factors that maintain stem cell populations and support the development of hematopoietic precursors and immature B cells (3-6). Using these advances recent sub-setting of stromal and precursor populations in the BM has provided insights into their behavior in the endosteal and perivascular compartments (3-6). In addition to the central role of the BM in maintaining immune homeostasis the ability to generate and mobilize immune cells in response to infection is a key function of this system. Notably emergency granulopoiesis and rapid mobilization of neutrophils from the BM is key for resistance to many pathogens. Similarly increased erythropoiesis can be a physiological response ABT-737 to acute inflammation but certain Rabbit polyclonal to Cannabinoid R2. infections can lead to the depletion of erythroid precursors and the development of anemia. The overarching goal of this review is to discuss the role of the BM niche in the host response to infection illustrate the ABT-737 impact of ABT-737 infectious diseases on this compartment and highlight some of the major questions in the field. Hematopoiesis and the HSC niche Hematopoiesis is the process by which hematopoietic stem cells (HSC) differentiate into immune cells through a series of lineage commitments. Lineageneg Sca-1+ ckit+ cells (LSKs reviewed extensively in (7-9)) include the earliest hematopoietic precursors in the BM with the potential to develop into multiple lineage-specific progenitors such as common lymphoid and myeloid progenitors ABT-737 and megakaryocyte or erythrocytic precursors (Figure 1). Of note only a small percentage of LSKs are HSCs; the majority of the LSK population represents a variety of multipotent or lineage committed cells. At steady state this differentiation is a complex but well-ordered process leading to the development of lymphocytes granulocytes and myeloid cells. Figure 1 Hematopoietic stem cell responses to infection. (A-C). Potential routes of pathogen sensing by HSCs. (A) HSCs in the BM can express PRRs such as TLRs thus when the BM is directly infected these cells may recognize pathogen-derived antigen … Given the diverse functions of the BM it is not surprising that this organ is comprised of distinct anatomical compartments. For example within the BM HSCs are distributed primarily in or near the endosteal region or the interface between medullary bone and stromal cells (Figure 1). This is a site with a distinctive micro-anatomic circulatory system though recent evidence indicates that perivascular niches also support HSC populations (6). The retention of HSCs in this environment is thought to promote survival and/or maintain hematopoietic progenitors in the quiescent G0 phase of the cell cycle allowing these cells to self renew and offering a ready pool of cells for rapid emergence (10-12). The direct interactions between vascular stromal cells and nestin-negative mesenchymal progenitors and between osteoblastic cells and HSCs themselves promote HSC survival and control niche size (5 13 Several chemokines and adhesion molecules notably CXCL12 and VLA-4 (14) contribute to HSC localization and maintenance and the local production of SCF by mesenchymal and perivascular stromal cells as well as endothelial cells promotes the generation and maintenance of HSCs (6). Perhaps the best-studied chemokine-receptor pair in this process is CXCL12-CXCR4 and disruption of this pathway leads to alterations in cellular retention in the BM including mobilization of early lymphoid progenitors and HSCs (14 15 However these cell types occupy distinct niches populated by discrete populations of CXCL12-producing cells (16). Thus expression of CXCL12 by endothelial cells.