Studies over the last decade uncovered overlapping niches for hematopoietic stem cells (HSCs), multipotent progenitor cells, common lymphoid progenitors, and early B cell progenitors. activity can be regulated by the quality and quantity of hematopoietic progenitors being produced. For example, pre-leukemic B cell progenitors and preB acute ARRY334543 (Varlitinib) lymphoblastic leukemias interact directly with MPCs, and downregulate IL-7 expression and the production of non-leukemic lymphoid cells. In this review, we discuss a novel model of B cell development that is centered on cellular circuits ARRY334543 (Varlitinib) formed between B cell progenitors and lymphopoietic niches. 1C.?Introduction The immune system is composed of multiple cell types produced in primary lymphoid organs. With the exception of T cells, all other blood cell types develop from hematopoietic progenitor cells in the bone marrow. In humans, the bone marrow produces about 200 billion blood cells daily, of which 90% are red blood cells, and the remaining 10% being composed of granulocytes (neutrophils being the most abundant), monocytes, dendritic cell precursors, lymphocytes, and platelets. This remarkable capacity to produce large numbers of distinct cell types with specialized functions is, perhaps, unmatched by any other organ in adult mammals. Besides ensuring daily blood cell production, specialized microenvironments in the bone marrow also contribute to the long-term maintenance of two types of stem cells, hematopoietic stem cells (HSCs) and mesenchymal stem and progenitor cells (1, 2), and to other differentiated cells, such as memory T cell subsets and antibody producing plasma cells (3), that are critical for ensuring long-term immunity against previously encountered antigens. Hematopoietic cells are commonly separated into two major lineages, lymphoid and myeloid, with each lineage composed by multiple cell subsets with different cellular functions, distribution throughout the body, ARRY334543 (Varlitinib) and life spans. Lymphoid lineage cells, for example, develop from a common lymphoid progenitor (CLP) that has lost the capacity to differentiate into myeloid cells, but still retains the ability to differentiate into multiple types of lymphocytes. B lymphocytes are the most abundant lymphocyte subset produced in bone marrow (20%), followed by NK cells (5%), and some subsets of innate lymphoid cells (ILCs, 1%). Although T cell development takes place in the thymus, a CLP subset with thymus-homing capacity periodically exits the bone marrow to seed the thymus and initiate T cell development (4). Similarly, the common myeloid progenitor (CMP) can differentiate into all types of myeloid cells, with erythroid cells and granulocyte subsets being the most abundant, followed by monocytes, dendritic cell precursors, and megakaryocytes. The diversity of hematopoietic cells that are produced on a daily basis is dependent on a limited number of lineage instructive extracellular signals and/or growth factors. For example, T and B lymphoid lineages, and some ILC subsets, are almost strictly dependent on interleukin (IL)-7 for proper development in the adult bone marrow (5-7), while NK cell development requires IL-15 (8). Likewise, the cytokines Granulocyte-Colony Stimulating Factor (GCSF), Granulocyte-Monocyte Colony Stimulating Factor (GMCSF), and Macrophage Colony Timp2 Stimulating Factor (MCSF) are critical for granulocyte, monocyte, and macrophage production, whereas thrombopoietin and erythropoietin stimulate megakaryocyte and erythroid cell development. Although lymphoid and myeloid cytokines are not exclusively produced by cells residing in the bone marrow, they act on hematopoietic progenitor cells that are predominantly localized in ARRY334543 (Varlitinib) this organ. Furthermore, some of these cytokines are produced in limiting amounts, such as IL-7 and IL-15, and consumed by several types of cells (e.g. B cells, T cells, ILC subsets), making the bioavailability of lymphopoietic cytokines restricted to the niche that produces them. Lymphocyte progenitors require specific migratory cues, specifically CXCR4 and its ligand CXCL12, in order to localize near or in contact with cells that produce lymphopoietic cytokines (9). Although, a clear understanding of how myeloid cells are organized during development in bone marrow is still lacking, several studies suggest that specialized niches also exist for granulocyte monocyte precursors (GMPs), for osteoclast precursors, for megakaryocytes, and for erythrocyte production (10-14). In the case of osteoclast development, the finals steps are coordinated by oxysterol ligands of EBI2 (Gpr183) most likely produced by osteoblasts, which attract osteoclast progenitor cells to endosteal niches (12). These observations demonstrate that hematopoietic cell development is coordinated by chemotactic cues that guide distinct progenitor cells to specialized niches for differentiation. One of the most studied bone marrow niches is the HSC niche. Initial studies pointed at osteoblasts forming the HSC niche (15, 16). However, recent studies characterized the HSC.