Heterogeneity of the bone marrow niche

Abstract

Purpose of review: The bone marrow niche is increasingly recognized as heterogeneous with specific subtypes of mesenchymal niche cells governing the development or homeostasis of selective parenchymal hematopoietic subsets. The present review outlines recent efforts in dissecting these microniches regulated by unique cell pairings within the bone marrow and provides an overview of how the bone marrow orchestrates multiple facets of hematopoiesis.

Recent findings: Recent advancement in technologies has significantly improved our understanding of the cellular and molecular constituents that contribute to regulation of hematopoiesis and to maintenance of the hematopoietic stem cells (HSCs). Transgenic mouse models that enable endogenous cell deletion or lineage tracing, coupled with advanced intravital microscopy has identified several mesenchymal cell types, including the osteolineage cells, megakaryocytes, macrophages, perivascular cells, and Schwann cells, to be indispensible regulators of hematopoiesis. These niche cells, when perturbed, each caused very specific hematopoietic consequences including impairment in B-cell maturation, T lineage development, erythropoiesis, and impact different aspects of HSC behavior such as quiescence, mobilization, and response to acute stress signals.

Summary: The emerging concept is that the bone marrow environment is composed of multiple microniches, each consisting of unique pairing of distinct supportive stromal cells with distinct hematopoietic subtypes to regulate a particular branch of hematopoietic cell process. The bone marrow can be viewed as a carrier with subcompartments tailored to support different hematopoietic activities.

Figure 1.

Illustration of Osx⁺ cell regulation of B cell maturation and Ocn⁺ cell control of T lymphopoiesis. Osx⁺ osteoprogenitors produce IL7 to mediate early pre-pro B to pro B development and secret IGF1 to promote later stage of pro B to pre B transition. Deletion of Osx⁺ cells in transgenic mice led to a failure of B cell maturation at the pro B to pre B transition stage. Administration of IGF1, but not IL7, was able to fully rescue B cell deficiency, suggesting that IGF1 production by Osx⁺ cells is necessary for late stage B cell differentiation while IL7, which mediate early B cell development, is supplemented by Osx⁺ cells but also provided by additional stromal subtypes in the bone marrow. On the other hand, Ocn⁺ mature osteoblasts and osteocytes regulate T lineage cell development. Endogenous depletion of Ocn⁺ cells or Ocn⁺ cell-specific deletion of the Notch ligand DLL4, results in loss of T lineage cells. Ocn⁺ cells express DLL4, which binds and activates Notch receptors on common lymphoid progenitors (CLPs). This cell-cell communication ensures adequate production of T-cell competent CLPs (Ly6D- CLPs) and the expression of chemotactic molecules, CCR7 and PSGL1, on T progenitor cell surface necessary for subsequent thymic seeding and downstream T cell development. Abbreviations: hematopoietic stem cell (HSC), multipotent progenitor (MPP), common lymphoid progenitor (CLP), early T-cell precursor (ETP), double negative (DN), double positive (DP), single positive (SP), delta-like 4 (DLL4), interleukin 7 (IL7), insultin-like growth factor 1 (IGF1), C-C chemokine receptor type 7 (CCR7), P-selectin glycoprotein ligand-1 (PSGL1).

Figure 2.

Schematic representation of erythroblastic island. Erythroblastic island consists of a central CD169-expressing macrophage and adherent erythroblasts at varying stages of differentiation. The central macrophage regulates many steps of erythropoiesis through direct interactions with developing erythroblasts and secretion of factors such as IL6, TGFβ, TRAIL, and TNFα to promote erythropoiesis. The macrophage not only provides iron for developing erythroblasts but also phagocytoses expelled nuclei. Young, multilobulated reticulocytes are initially attached to the macrophage surface but later detach. Abbreviations: interleukin 6 (IL6), transforming growth factor beta (TGFβ), tumor necrosis factor-related apoptosis-incuding ligand (TRAIL), tumor necrosis factor alpha (TNFα).