Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche

Abstract

The mechanisms of bone and blood formation have traditionally been viewed as distinct, unrelated processes, but compelling evidence suggests that they are intertwined. Based on observations that hematopoietic precursors reside close to endosteal surfaces, it was hypothesized that osteoblasts play a central role in hematopoiesis, and it has been shown that osteoblasts produce many factors essential for the survival, renewal, and maturation of hematopoietic stem cells (HSCs). Preceding these observations are studies demonstrating that the disruption or perturbation of normal osteoblastic function has a profound and central role in defining the operational structure of the HSC niche. These observations provide a glimpse of the dimensions and ramifications of HSC-osteoblast interactions. Although more research is required to secure a broader grasp of the molecular mechanisms that govern blood and bone biology, the central role for osteoblasts in hematopoietic stem cell regulation is reviewed herein from the perspectives of (1) historical context; (2) the role of the osteoblast in supporting stem cell survival, proliferation, and maintenance; (3) the participation, if any, of osteoblasts in the creation of a stem cell niche; (4) the molecules that mediate HSC-osteoblast interactions; (5) the role of osteoblasts in stem cell transplantation; and (6) Introduction and historical perspectiveHematopoiesis occurs in unique microenvironments that facilitate the maintenance of hematopoietic stem cells (HSCs) as pluripotent and support the maturation of progenitors. Each of these activities may require different growth factors and microenvironments, the identities of which have yet to be determined. In vitro, bone marrow stromal cells (BMSCs) serve as a rich source of growth factors for a variety of hematopoietic processes. BMSCs are composed of several different populations, including fibroblasts, macrophages, endothelial cells, and adipocytes. Although it is difficult to discern the relative importance of each of these cells, it has been shown that direct stromal cell-blood cell contact, BMSC production of the extracellular bone marrow matrix, and cytokine synthesis are all relevant to the formation and maturation of blood cells in vitro. [1][2][3] The role of BMSCs in vivo is less clear.Osteoblasts have long been known to play a central role in skeletal development. Derived from pluripotent mesenchymal stem cells (MSCs), they mature along a specific lineage to become highly specialized synthetic cells. As such, osteoblasts respond to many mechanical, local, and systemic stimuli that facilitate mineralization while they orchestrate bone remodeling. Osteoblasts also constitute part of the stromal cell support system in marrow, but little is known about their functional relevance to HSCs. Early attempts to understand this relationship focused on the protective function that bone might serve for the hematopoietic organ. 4 Observations in birds of recurrent trabeculation of the medullary cavity during ovulation show that the h...

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

“…Disruption of the SDF-1/CXCR4 axis has been reported to lead to stem cell mobilization in several animal models (see [18][19][20][21] ). The comparison of data obtained using an animal model and by studying patients with PMF provides evidence that alterations in CXCR4 expression or SDF-1 levels may be, at least partially, responsible for the abnormal stem/progenitor cell trafficking observed in PMF.…”

“…In addition to the liver, SDF-1 is produced in the marrow by several cell types, including osteoblasts 17 . Recent genetic studies have demonstrated that osteoblasts are critical cellular elements for stem cell maintenance and development [18][19][20] . Stem cells are believed to reside in close proximity to the endosteal surface of the bone, where osteoblasts are also located 21,22 .…”

Interleukin 32 promotes hematopoietic progenitor expansion and attenuates bone marrow cytotoxicity

“…OPG is secreted by osteoblasts within the stem cell niche [33] and inhibits the differentiation of osteoclasts [34]. Induction of cell proliferation does not belong to its known qualities.…”

Homing of Cancer Cells to the Bone

“…VLA-4 integrin deregulation is consistently found in solid tumors and in AML and has shown to be responsible for tumor drug resistance [114][115][116][117]. VLA-4 and its ligand fibronectin are also important for HSC localization and retention to osteoblasts and the endosteal niche [118,119].…”