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Journal ArticleDOI

Mesenchymal and haematopoietic stem cells form a unique bone marrow niche

TL;DR: It is demonstrated that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
Abstract: The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

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Citations
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Journal ArticleDOI
TL;DR: The mechanisms that control monocyte trafficking under homeostatic, infectious and inflammatory conditions are being unravelled and are the focus of this Review.
Abstract: Monocytes originate from progenitors in the bone marrow and traffic via the bloodstream to peripheral tissues. During both homeostasis and inflammation, circulating monocytes leave the bloodstream and migrate into tissues where, following conditioning by local growth factors, pro-inflammatory cytokines and microbial products, they differentiate into macrophage or dendritic cell populations. Recruitment of monocytes is essential for effective control and clearance of viral, bacterial, fungal and protozoal infections, but recruited monocytes also contribute to the pathogenesis of inflammatory and degenerative diseases. The mechanisms that control monocyte trafficking under homeostatic, infectious and inflammatory conditions are being unravelled and are the focus of this Review.

2,309 citations

Journal ArticleDOI
16 Jan 2014-Nature
TL;DR: The haematopoietic stem cell niche remains incompletely defined and beset by competing models, and outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.
Abstract: Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.

1,899 citations

Journal ArticleDOI
26 Jan 2012-Nature
TL;DR: HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance, and were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (Lepr)-expressing periv vascular stromal cells.
Abstract: Several cell types have been proposed to create niches for haematopoietic stem cells (HSCs). However, the expression patterns of HSC maintenance factors have not been systematically studied and no such factor has been conditionally deleted from any candidate niche cell. Thus, the cellular sources of these factors are undetermined. Stem cell factor (SCF; also known as KITL) is a key niche component that maintains HSCs. Here, using Scf(gfp) knock-in mice, we found that Scf was primarily expressed by perivascular cells throughout the bone marrow. HSC frequency and function were not affected when Scf was conditionally deleted from haematopoietic cells, osteoblasts, nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (Lepr)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Thus, HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

1,649 citations

Journal ArticleDOI
14 Mar 2013-Nature
TL;DR: It is suggested that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stroma cells in the perivascular region, including endothelial cells and mesenchymal progenitor, supports HSCs.
Abstract: Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells, CXCL12-abundant reticular cells, leptin-receptor-positive stromal cells, and nestin-green fluorescent protein (GFP)-positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C-X-C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1-cre (Prx1 also known as Prrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.

1,069 citations

Journal ArticleDOI
TL;DR: Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases.
Abstract: When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour–bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases.

1,067 citations

References
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Journal ArticleDOI
23 Oct 2003-Nature
TL;DR: Osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation.
Abstract: Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.

3,434 citations

Journal ArticleDOI
11 Jan 2002-Cell
TL;DR: It is proposed that Runx2/Cbfa1-expressing preosteoblasts are still bipotential cells, because Osx null preostEoblasts express typical chondrocyte marker genes, and Osx acts downstream of Runx 2/C bfa1.

3,283 citations

Journal ArticleDOI
01 Jul 2005-Cell
TL;DR: This work compared the gene expression profiles of highly purified HSCs and non-self-renewing multipotent hematopoietic progenitors and found that both groups occupied multiple niches, including sinusoidal endothelium in diverse tissues.

3,091 citations

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