Review
What is the true nature of the osteoblastic hematopoietic stem cell niche?

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The recently revitalized interest in the regulation of hematopoietic stem cells (HSCs) by the bone marrow microenvironment has resulted in the identification of some important cell types that potentially form the HSC niche. The term ‘osteoblast’ has commonly been used to describe the endosteal elements of the HSC niche, but these cells are part of a larger family that functions in bone at different stages of differentiation. Given that there is much controversy as to what cell types have important roles in the HSC niche, this review offers an overview of the diverse osteoblastic cell types and discusses the current evidence regarding what roles they have in the HSC niche.

Section snippets

The identification of the adult hematopoietic stem cell niche

The bone marrow (BM) cavity serves as the main site of hematopoiesis in the human adult. This lifelong process of constant replenishment of mature hematopoietic cells is sustained by the hematopoietic stem cells (HSCs). To accomplish this, it is thought that HSCs have the potential to self-renew to maintain the HSC pool. In 1978, Schofield proposed that HSCs needed to be localized in a particular location (termed the HSC niche) within the BM to retain their multipotency [1] and that if the HSCs

Roles of cells of the osteoblast lineage in the HSC niche

The development of long-term BM cultures in the 1970s described methods whereby hematopoiesis could be sustained in culture for many months [17]. The success of this culture system relied on the development of adherent cells, termed ‘stromal cells’. The identity of the different types of stromal cells remained elusive; however, these stromal cells expressed alkaline phosphatase (an enzyme present in, but not exclusive to, osteoblast lineage cells) [18]. Almost 20 years later, a series of

Misleading terminology in describing the HSC niche

As has been raised recently by Bianco [23], the term ‘osteoblastic niche’ is oversimplified and potentially incorrect in regard to which cells actively regulate HSC maintenance and self-renewal. Researchers have used the generic term ‘osteoblasts’ to refer to a spectrum of cell types of the osteoblastic lineage. However, osteoblasts are a well-defined population of differentiated cells actively involved in bone formation. The terminology ‘endosteal niche’ is also misrepresentative because the

Skeletal stem cells, adventitial reticular cells and pre-osteoblasts

In postnatal stages, the osteoblast lineage is derived from mesenchymal stem cells (MSCs). A population of MSCs can be obtained from bone marrow stromal cells (BMSCs), non-hematopoietic cells that adhere to cell culture dishes. The cells that give rise to these plastic-adherent colonies were originally identified as colony-forming fibroblasts (CFU-F) [25], and progeny of single bone-marrow-derived CFU-F differentiate into osteoblast-lineage cells, cartilage cells (chondrocytes) or adipocytes

Osteoblasts and bone lining cells

The committed osteoblast population is heterogeneous, and there are at least two structurally and functionally distinct subpopulations that cover the endosteal bone surface: osteoblasts and bone lining cells [36]. Bone lining cells are frequently overlooked in studies of the HSC niche because mononuclear cells surrounding bone are commonly referred to as osteoblasts. Although both cell types are always found in close contact with the bone surface, both at the endosteum (marrow surface of bone)

Studies linking HSCs and the osteoblast lineage: which cells of the osteoblast lineage comprise the HSC niche?

The two pioneering studies describing the osteoblastic HSC niche reported that an increase in the amount of trabecular bone and/or trabecular osteoblasts correlated with increased HSC numbers 3, 4. A subsequent study demonstrated that ablating osteoblast-lineage cells in vivo resulted in relocation of most HSCs from the BM into the extramedullary sites such as spleen and liver [22]. These studies have, importantly, directed attention to the previously understudied roles of the microenvironment

PTH/PTHrP receptor in cells of the microenvironment

The mouse Col1a1 2.3kB promoter was used to generate transgenic mice in which osteoblasts express the constitutively active PTH/parathyroid hormone-related protein (PTHrP) receptor [47]. Bone histomorphometry revealed increased trabecular bone volume, with increased numbers of osteoblasts, osteoclasts and fibrotic stroma-like cells [47]. In situ hybridization showed that the fibrotic cells expressed alkaline phosphatase and other markers of the osteoblast lineage, including osteopontin [47].

Impact of Bmpr1a loss in cells of the microenvironment

The bone morphogenetic proteins (BMPs) have been shown to be important in regulating HSC specification during embryonic development and, also, in regulating the proliferation of adult HSCs [49]. To investigate its potential role in regulating adult HSCs, Bmpr1a was conditionally deleted in murine hematopoietic and BM stromal cells using myxovirus resistance 1-Cre (Mx1-Cre) [4]. There was an increase in ectopic bone formation after the deletion, accompanied by increased numbers of osteoblasts [4]

Other candidate HSC niches of the osteoblast lineage

The relationship and function of Nestin+CD45 cells [35], α-SMAGFP+ cells 33, 34 and SSCs is also of interest. Although extensive studies have not yet examined these candidate HSC niche cells, preliminary studies have shown that Nestin+CD45 cells express mRNA for proteins shown to regulate HSCs, including CXCL12, SCF and angiopoietin-1 (Ang-1) 15, 35. Furthermore, human SSCs have been shown to express high levels of mRNA for N-cadherin, Jagged-1, CXCL12, SCF and Ang-1 [27]. These cells could

Concluding remarks

Precursors of the osteoblast lineage, such as pre-osteoblasts and SSCs, express molecules shown to be important for HSC regulation (such as CXCL12, Ang-1 and SCF) and might play an active part in the HSC niche. Indeed, stromal cells that support hematopoiesis are reminiscent of immature osteoblasts and are grown in culture conditions in which spontaneous mature osteoblast cell differentiation does not normally occur 17, 18, 19, 20, 21. In contrast, mature cells of the osteoblast lineage

Acknowledgements

We thank C.R. Walkley and D.T. Scadden for critically reviewing the manuscript. M.A. is a Swedish Research Council Post-doctoral Fellow, N.A.S is a Senior Research Fellow of the National Health and Medical Research Council (NHMRC), T.J.M. is a John Holt Fellow and L.E.P. is an NHMRC RD Wright Fellow.

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