• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Support Palliat Care. Author manuscript; available in PMC Sep 1, 2009.
Published in final edited form as:
Curr Opin Support Palliat Care. Sep 2008; 2(3): 211–217.
doi:  10.1097/SPC.0b013e32830d5c12
PMCID: PMC2572865
NIHMSID: NIHMS71866

Hematopoietic niche and bone meet

Abstract

Purpose of review

To provide an overview of the hematopoietic stem cell (HSC) niche in the bone marrow. In addition to highlighting recent advances in the field, we will also discuss components of the niche that may contribute to the development of cancer, or cancer metastases to the bone.

Recent findings

Much progress has been very recently made in the understanding of the cellular and molecular interactions in the HSC microenvironment. These recent findings point out the extraordinary complexity of the HSC microenvironment. Emerging data also suggest convergence of signals important for HSC and for leukemia or metastatic disease support.

Summary

The HSC niche comprises complex interactions between multiple cell types and molecules requiring cell-cell signaling as well as local secretion. These components can be thought of as therapeutic targets not only for HSC expansion, but also to modify behavior of hematopoietic malignancies and cancer metastases to the bone.

Keywords: hematopoietic stem cells, niche, notch

Introduction

The hematopoietic stem cell (HSC) microenvironment or niche regulates critical HSC fate decisions. Over the last year, the complexity of the niche, with its cellular and noncellular components, has continued to come into focus. Moreover, emerging evidence begins to suggest involvement of the niche in leukemia stem cells and also in bone metastatic disease derived from solid tumors such as cancers of the breast.

Cellular components of the hematopoietic stem cell niche

Schofield [1] first hypothesized that the microenvironment may provide regulatory signals to HSCs. However, the cellular components of the bone marrow microenvironment were not identified for another 20 years. Human bone-forming cells, or osteoblasts, produce important hematopoietic cytokines (granulocyte colony-stimulating factor or G-CSF, granulocyte macrophage colony-stimulating factor, and leukemia inhibitory factor) [2,3], can support HSCs in vitro and have the ability to maintain long-term culture initiating cells (LTC-ICs), primitive self-renewing hematopoietic cells [4]. Osteoblasts also improve engraftment during an allogeneic transplant when coinjected with HSCs [5]. To add to these early data, labeled HSCs transplanted in vivo preferentially engraft near the endosteum, where osteoblasts are also found [6]. Genetic data from our laboratory demonstrate that mice expressing constitutively active parathyroid hormone (PTH) and parathyroid-related peptide receptor (PTH1R) on osteoblasts (Col1-caPTH1R mice) display an increase in osteoblast number, trabecular bone volume, and HSC number. These data establish that targeted activation of osteoblastic cells alone is sufficient to modify HSC behavior. PTH treatment also expanded HSC numbers in vivo. As the PTH1R is not expressed in HSCs [7••], these data also implicate a microenvironmentally mediated effect [8]. Further in-vitro coculture experiments demonstrated that cell-cell contact is required for PTH to expand HSCs. Taken together, these data strongly suggest that osteoblasts are key regulators of HSCs, and that close contact of osteoblasts and HSCs is required for this effect. Conditional inactivation of bone morphogenic protein receptor 1A (BMPR1A), which is also not expressed in HSCs, again resulted in an increase in both osteoblasts and HSCs [9]. The same study suggested that HSCs are in contact with spindle-shaped N-CAD-positive osteoblasts on the endosteal surface. In a different in-vitro model, induced osteoblast deficiency caused a loss of hematopoietic progenitors in the marrow and a transfer of hematopoiesis to the spleen [10]. These data taken together with the earlier in-vitro work strongly implicate osteoblasts as a major component of what has been termed the endosteal niche (Fig. 1).

Figure 1
Proposed molecular mechanisms for osteoblastic regulation of hematopoietic stem cell differentiation and self-renewal

More recent data have suggested that the niche provided by osteoblasts maintains HSCs in a quiescent state. A recent study demonstrated that the typical procedure used to flush the marrow from the bone leaves behind a significant population of HSCs adhered tightly to the endosteum [11•• ]. Endosteum-adhered HSCs isolated by grinding the bone and enzymatically digesting the bone fragments have increased proliferative and long-term engraftment potential as compared with HSCs flushed from the central marrow, suggesting that the endosteal microenvironment provides quiescence signals.

Endothelial cells are also proposed to be important in the HSC microenvironment. In-vivo and tissue section imaging localizes HSCs next to endothelial cells [12,13]. Also, endothelial cells secrete soluble factors that can expand human primitive hematopoietic cells ex vivo [14]. However, endothelial cells have not yet been shown to be a necessary regulatory component of the HSC microenvironment in vivo.

Osteoclasts, specialized bone resorbing cells of hematopoietic origin, have also been proposed as components of the HSC microenvironment. Activation of osteoclasts increases the mobilization of hematopoietic progenitors into the circulation [15], and inhibition of osteoclastic activity by strontium, which in fact increases bone and osteoblasts, leads to delayed hematopoietic recovery following bone marrow transplantation in mice [16•].

Neurons of the sympathetic nervous system (SNS) were also recently implicated in HSC regulation. Mice lacking ceramide galactosyltransferase cannot produce the myelin sheath component galactocerebrosides, and have defects in the mobilization response of HSCs to G-CSF. Normally, in response to G-CSF, neurons of the SNS signal to osteoblasts, which downregulate chemokine (C-X-C motif) ligand 12 (CXCL12) resulting in a subsequent mobilization of HSCs out of the marrow [17]. Moreover, chemical lesioning of the SNS with 6-hydroxydopamine (6OHDA) reduces the circadian rhythm controlled release of HSCs into the circulation. Similarly, sympathectomy of the tibiae in mice altered CXCL12 expression locally, but not in the contralateral sham-operated tibiae of the same mice [18••], suggesting that local CXCL12 expression is controlled by neural innervation.

Adipocytes are very abundant in the bone marrow, but it is not known if they provide HSCs regulation. Recent data suggest that adipocyte products can affect HSC behavior. Specifically, the adipokine adiponectin increases murine HSC proliferation whereas maintaining HSCs undifferentiated in vitro. In addition, deletion of the adiponectin receptor AdipoR1 reduces HSCs reconstitution potential [19•]. However, though adiponectin expression was originally identified in adipocytes [20], it has more recently been demonstrated to also be a product of osteoblasts [21]. Whether one or both cell types are responsible for adiponectin-mediated regulation of HSCs remains to be seen.

Molecular components of the niche

Regulation of cell fate decisions is an important function of the HSC niche. Our laboratory and others have provided evidence for the Notch signaling pathway’s involvement in this regulatory function. Notch signaling influences cell fate decisions in many systems and is very important during development [22,23]. In HSCs, Notch signaling is important in the regulation of self-renewal [24-29]. Specifically, the Notch ligand Jagged1 (Jag1) is sufficient for stroma-dependent expansion of human HSCs [30]. Components of Notch signaling are present on multiple cell types in the bone marrow, in fact the importance of osteoblastic and osteoclastic Notch signaling has been demonstrated by our own laboratory and others [31-39]. Notch signaling was implicated in the osteoblastic-dependent increase of HSCs in the Col1-caPTH1R mice as there was an increase in the activated form of Notch1 in HSCs, and γ-secretase inhibition attenuated the observed increase in HSCs [8]. Intermittent PTH treatment of mice increases expression of Jag1 in trabecular and endosteal spindle-shaped osteoblasts and in osteoblastic UMR106 cells through the adenylate cyclase and protein kinase A (AC/PKA) pathway [39]. Recent data challenge the importance of canonical Notch signaling in HSC maintenance [40••]. However, whether Notch signaling is required for osteoblastic HSC expansion is not known.

To allow for cell-cell interactions within the niche, HSCs must be physically attached to at least some niche components through cell adhesion mechanisms. A number of mechanisms have been implicated in HSC homing to and maintenance in the niche, such as the binding of CD44 and integrin family proteins to osteopontin, and the binding of integrins to fibronectin and vascular cell adhesion molecule 1 (VCAM1) [41-48]. Integrin binding involves heterodimers of integrin family proteins on the cell surface, which bind to extracellular ligands such as fibronectin. Signaling through integrins protects HSCs from apoptosis, maintaining HSCs in a more quiescent state [49,50]. Binding of HSCs to fibronectin through the integrin molecules very late antigen-4 (VLA-4) and VLA-5 maintains undifferentiated HSCs [51•]. Further, the retention of LTC-IC capability in human hematopoietic progenitor cells (HPCs) appears to be mediated by β-integrins [52•].

N-CAD, a member of the cadherin family of adhesion molecules is another molecule implicated in HSC regulation. Osteoblasts comprising the HSC niche were shown to express N-CAD that dimerized with N-CAD on the surface of HSCs [53,54] to form an adherens junction [9]. However, there is controversy over whether N-CAD is expressed on HSCs or not [55••,56••].

Annexin II (Anxa2) is a regulator of cell motility and a recently identified novel modulator of the HSC niche expressed by endosteal osteoblasts as well as marrow endothelium. Anxa2 inhibitors impair HSC homing and engraftment, and there is loss of HSCs in the bone marrow of Anxa2-deficient mice [57••].

An additional signaling pathway that promotes the maintenance of HSCs in the marrow is the receptor tyrosine kinase Tie2 and its ligand angiopoietin-1 (Ang-1). Tie2-positive cells in the fetal liver contain the long-term repopulating capacity of HSCs [58], and mice with a combined Tie1 and Tie2 deletion are unable to maintain HSCs in the adult marrow [59]. Osteoblasts produce Ang-1 [60] and the interaction between Tie2 expressed on HSCs, and Ang-1 results in increased quiescence, stronger adhesion to bone and greater protection from injury [53]. Tie2 and Ang-1 signaling also increases expression of β1 Integrins as well as N-CAD [61].

Soluble components of the niche

Stromal cell-derived factor-1 (SDF1) or CXCL12 is a member of the CXC motif family of chemokines and is produced by osteoblasts and endothelial cells in the bone marrow [62]. Binding of CXCL12 to its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is important in promoting HSC homing to and retention in the bone marrow [15,63-67]. PTH regulates CXCL12 in osteoblasts [8,68] and mice lacking CXCL12 have fetal hematopoietic defects [69,70]. CXCL12 also plays a role in promoting HSC quiescence, as adult mice with an induced deletion of CXCR4 have a higher proportion of HSCs exiting G0 and entering the cell cycle. Interestingly, knock-in studies identify a subset of cells in the marrow with abundant CXCL12 expression (named CAR, or CXCL12 abundant reticular cells). These cells are described as ‘reticular’ as they form a network in the marrow with long processes extending from the cell bodies. HSCs are closely associated with CAR cells, which are surrounded by endothelial cells, potentially identifying another cellular component of the HSC niche. Interestingly, CAR cells also express a high level of Jag1 [66]. Additional recent data support a central role of CXCL12 in HSC homing and retention in the bone marrow [18••,71•]. Although CXCL12 binds both CXCR4 and chemokine (C-X-C motif) receptor 7 (CXCR7) in vivo, data suggest that CXCR4 is the required receptor for CXCL12 in hematopoiesis [72•]. The question remains whether CXCL12 is directly responsible for promoting HSCs quiescence or whether CXCL12 directs HSCs to the niche where subsequent interactions promote quiescence.

Prostaglandin E2 (PGE2) is a soluble factor locally produced by osteoblasts [73] recently shown to be important in HSC regulation. PGE2 is an arachidonic acid derivative and is an important mediator of inflammation. Treatment of zebrafish with PGE2-related chemicals expands HSCs. Murine bone marrow treated ex vivo with 16,16-dimethyl-PGE2 and subsequently transplanted into irradiated recipients increased the number of spleen colony-forming units three-fold at 12 days after transplant [74••]. Interestingly, PTH is also one of the main stimulators of PGE2 in osteoblasts [75], suggesting PGE2 as a potential mediator of the PTH-dependent HSC increase.

Wnt signaling regulates cell fate in many mammalian systems, with the Wnt ligand signaling through its receptor frizzled and a coreceptor low-density lipoprotein receptor-related protein (LRP). Canonical Wnt signaling activates β-catenin, which signals to the nucleus. Wnt signaling increases HSC self-renewal with overexpression of activated β-catenin expanding the pool of HSCs in long-term cultures by both phenotype and function [76,77]. Also, in-vivo treatment with Wnt5A conditioned medium in mice increases the engraftment of human repopulating hematopoietic cells [78]. Osteoblasts have recently been implicated in Wnt-dependent HSC regulation, similarly to the action of osteoblasts in modulating the differentiation state of mesenchymal stem cells through Wnt signaling [79]. Osteoblastic overexpression of Dickkopf1 (Dkk1), an inhibitor of canonical Wnt signaling, inhibits Wnt signaling in HSCs, causing a defect in bone marrow repopulation after transplantation. As Dkk1 is endogenously expressed by osteoblasts, this suggests a means for osteoblasts to regulate Wnt signaling in HSCs [80••]. Recent data also suggest that noncanonical Wnt signaling regulates HSC fates [81•].

Interestingly, HSCs express the calcium-sensing receptor (CaR) and mice lacking CaR have defects in HSC homing to the endosteal niche [82]. Bone has a higher extracellular calcium ion concentration than other tissues [83] suggesting that HSCs may use the CaR to migrate up a calcium ion gradient and properly home to the marrow.

The hematopoietic stem cell niche and cancer

If the niche is mainly responsible for HSC regulation, then disruption of the microenvironment should lead to disregulation of HSC fate. Several lines of emerging data support this hypothesis. Retinoblastoma was recently shown to regulate interactions between HSC and the microenvironment. Conditional inactivation of retinoblastoma in either HSCs or the microenvironment alone is not sufficient to cause myeloproliferation or a loss of HSCs from the bone marrow. However, deletion of the retinoblastoma gene in both the microenvironment and hematopoietic cells leads to myeloproliferation and loss of HSCs from the bone marrow [84••]. A myeloproliferative syndrome also develops when the retinoic acid receptor γ (RARγ) is removed from the bone marrow microenvironment [85••].

Several components of the HSC niche have also been implicated in malignancies either as a niche for cancer stem cells or as fertile ground for the development of bone metastases. The β1 integrins, whose involvement in the HSC niche we discussed earlier, have been shown to protect cells from undergoing apoptosis induced by serum starvation [86]. β1 integrin is expressed in malignant cells and integrin-mediated adhesion of these cells can provide cell adhesion-mediated drug resistance (CAM-DR) [87-90,91•].

In addition to suggesting potential therapeutic targets, the presence of ligands that can adhere to niche components in cancer cells raises the question of whether malignant cells can occupy the same niche as HSCs. Homing signals for HSC may also home leukemia; leukemia cells express CXCR4 and have a transendothelial migration in response to CXCL12 just as normal HSCs [92,93]. Although the malignant niche for leukemia has yet to be identified, one recent study localized acute myelogenous leukemia (AML) stem cells displaying chemotherapy resistance to the bone marrow endosteum [94••]. Moreover, β-catenin conditional knockout in the hematopoietic system had impaired induction of chronic myelgenous leukemia (CML) in a breakpoint cluster region (BCR) and c-abl oncogene 1, receptor tyrosine kinase (ABL) model of leukemogenesis, owing to a deficiency of self-renewal in the CML stem cell population, suggesting that Wnt signaling is important not only in normal hematopoiesis but also in hematologic malignancies [95••].

One pathway that has been implicated in maintaining the quiescence of HSCs is the phosphatidylinisitol-3-OH kinase (PI(3)K)-Akt pathway. Loss of phosphatase and tensin homologue (PTEN), a repressor of the PI(3)K-Akt pathway, causes HSC activation resulting in an initial expansion of HSCs and an eventual decline over the long term. Another effect of PTEN deletion is the rapid development of leukemia [96•,97,98].

If it is possible for malignant cells to take advantage of the antiapoptotic properties of the HSC niche, then it may be possible to disrupt these interactions and sensitize these cells to chemotherapeutics. In fact, targeting adhesion-mediating molecules such as CD44 can eradicate human AML stem cells [99]. Inhibiting β1 integrins can overcome CAM-DR to sensitize AML cells to Ara-C [100•]. αvβ3 integrin is a mediator of breast cancer metastasis to the bone, and specific inhibition of its binding can significantly reduce bone colonization of cancer cells [101•].

Conclusion

The HSC microenvironment is critical in regulating the biology of hematopoiesis. The many exciting advances in the field of the HSC niche in the last year have improved our understanding of the many cellular and molecular interactions involved in the niche. Furthering our knowledge of the mechanisms of HSC regulation by the niche cannot only improve our ability to expand HSCs without losing their regenerative potential, but also may point to novel strategies for the treatment of hematologic malignancies and cancer metastases to bone.

Acknowledgements

The present work was supported by the National Institutes of Health (RO1 DK076876 to L.M.C.) and the Pew Foundation (L.M.C.). R.L.P is a trainee in the Medical Scientist Training Program, NIH T32 GM-07356.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 238-240).

1. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4:7–25. [PubMed]
2. Taichman RS, Emerson SG. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med. 1994;179:1677–1682. [PMC free article] [PubMed]
3. Marusic A, Kalinowski JF, Jastrzebski S, Lorenzo JA. Production of leukemia inhibitory factor mRNA and protein by malignant and immortalized bone cells. J Bone Miner Res. 1993;8:617–624. [PubMed]
4. Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996;87:518–524. [PubMed]
5. El-Badri NS, Wang BY, Cherry, Good RA. Osteoblasts promote engraftment of allogeneic hematopoietic stem cells. Exp Hematol. 1998;26:110–116. [PubMed]
6. Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood. 2001;97:2293–2299. [PubMed]
7••. Adams GB, Martin RP, Alley IR, et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol. 2007;25:238–243. [PubMed]
In this study, treatment of mice with PTH for 5 weeks prior to a 5-day mobilization with G-CSF increased the number of HSCs in circulation. PTH treatment after chemotherapy in mice also leads to a faster and more robust recovery of the HSC pool. These data validate the niche as a potential therapeutic target.
8. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–846. [PubMed]
9. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–841. [PubMed]
10. Visnjic D, Kalajzic Z, Rowe DW, et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004;103:3258–3264. [PubMed]
11••. Haylock DN, Williams B, Johnston HM, et al. Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum. Stem Cells. 2007;25:1062–1069. [PubMed]
HSCs adhered tightly to the endosteum are not recovered by conventional methods of flushing the marrow. Liberating these HSCs requires grinding of the bone with subsequent enzymatic digestion. HSCs isolated in this way demonstrate increased proliferative and long-term engraftment potential.
12. Kiel MJ, Yilmaz OH, Iwashita T, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–1121. [PubMed]
13. Sipkins DA, Wei X, Wu JW, et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature. 2005;435:969–973. [PMC free article] [PubMed]
14. Chute JP, Muramoto GG, Dressman HK, et al. Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis. Stem Cells. 2006;24:1315–1327. [PubMed]
15. Kollet O, Dar A, Shivtiel S, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12:657–664. [PubMed]
16•. Lymperi S, Horwood N, Marley S, et al. Strontium can increase some osteoblasts without increasing hematopoietic stem cells. Blood. 2008;111:1173–1181. [PubMed]
In-vivo treatment of mice with strontium increases osteoblastic number and bone volume. However, it fails to increase N-CAD expressing osteoblasts and HSCs. Suggesting N-CAD expressing osteoblastic involvement in HSCs support. Also it may suggest that osteoclasts (which are inhibited by strontium) may be involved in HSCs expansion and regulation.
17. Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006;124:407–421. [PubMed]
18••. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008;452:442–447. [PubMed]
The CXCL12 concentration is shown to be controlled by the circadian rhythm. This control regulated by photic cues is matched by circadian oscillations in circulating HSCs released from the bone marrow.
19•. DiMascio L, Voermans C, Uqoezwa M, et al. Identification of adiponectin as a novel hemopoietic stem cell growth factor. J Immunol. 2007;178:3511–3520. [PubMed]
Adiponectin is identified as a regulator of HSCs both in vivo and in vitro. Competitive transplants show that culture of HSCs with adiponectin prior to transplant increases their repopulation of lethally irradiated mice.
20. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995;270:26746–26749. [PubMed]
21. Berner HS, Lyngstadaas SP, Spahr A, et al. Adiponectin and its receptors are expressed in bone-forming cells. Bone. 2004;35:842–849. [PubMed]
22. Milner LA, Bigas A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood. 1999;93:2431–2448. [PubMed]
23. Lai EC. Notch signaling: control of cell communication and cell fate. Development. 2004;131:965–973. [PubMed]
24. Karanu FN, Murdoch B, Gallacher L, et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med. 2000;192:1365–1372. [PMC free article] [PubMed]
25. Karanu FN, Murdoch B, Miyabayashi T, et al. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hemato-poietic cells. Blood. 2001;97:1960–1967. [PubMed]
26. Karanu FN, Yuefei L, Gallacher L, et al. Differential response of primitive human CD34- and CD34+ hematopoietic cells to the Notch ligand Jagged-1. Leukemia. 2003;17:1366–1374. [PubMed]
27. Ohishi K, Varnum-Finney B, Bernstein ID. The notch pathway: modulation of cell fate decisions in hematopoiesis. Int J Hematol. 2002;75:449–459. [PubMed]
28. Shojaei F, Trowbridge J, Gallacher L, et al. Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior. Dev Cell. 2005;8:651–663. [PubMed]
29. Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000;6:1278–1281. [PubMed]
30. Li L, Milner LA, Deng Y, et al. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 1998;8:43–55. [PubMed]
31. Bolos V, Grego-Bessa J, de la Pompa JL. Notch signaling in development and cancer. Endocr Rev. 2007;28:339–363. [PubMed]
32. Deregowski V, Gazzerro E, Priest L, et al. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morpho-genetic protein signaling. J Biol Chem. 2006;281:6203–6210. [PubMed]
33. Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol. 2007;194:459–474. [PubMed]
34. Nobta M, Tsukazaki T, Shibata Y, et al. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem. 2005;280:15842–15848. [PubMed]
35. Pereira RM, Delany AM, Durant D, Canalis E. Cortisol regulates the expression of Notch in osteoblasts. J Cell Biochem. 2002;85:252–258. [PubMed]
36. Sciaudone M, Gazzerro E, Priest L, et al. Notch 1 impairs osteoblastic cell differentiation. Endocrinology. 2003;144:5631–5639. [PubMed]
37. Shindo K, Kawashima N, Sakamoto K, et al. Osteogenic differentiation of the mesenchymal progenitor cells, Kusa is suppressed by Notch signaling. Exp Cell Res. 2003;290:370–380. [PubMed]
38. Watanabe N, Tezuka Y, Matsuno K, et al. Suppression of differentiation and proliferation of early chondrogenic cells by Notch. J Bone Miner Metab. 2003;21:344–352. [PubMed]
39. Weber JM, Forsythe SR, Christianson CA, et al. Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells. Bone. 2006;39:485–493. [PubMed]
40••. Maillard I, Koch U, Dumortier A, et al. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell. 2008;2:356–366. [PMC free article] [PubMed]
The authors showed that the maintenance of normal adult hematopoiesis is not dependent on canonical Notch signaling. However, it remains to be shown whether Notch signaling is required for osteoblast-dependent HSC expansion.
41. Potocnik AJ, Brakebusch C, Fassler R. Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow. Immunity. 2000;12:653–663. [PubMed]
42. Vermeulen M, Le Pesteur F, Gagnerault MC, et al. Role of adhesion molecules in the homing and mobilization of murine hematopoietic stem and progenitor cells. Blood. 1998;92:894–900. [PubMed]
43. Wagers AJ, Allsopp RC, Weissman IL. Changes in integrin expression are associated with altered homing properties of Lin(-/lo)Thy1.1(lo)Sca-1(+)c-kit(+) hematopoietic stem cells following mobilization by cyclophosphamide/granulocyte colony-stimulating factor. Exp Hematol. 2002;30:176–185. [PubMed]
44. McKee MD, Farach-Carson MC, Butler WT, et al. Ultrastructural immunolocalization of noncollagenous (osteopontin and osteocalcin) and plasma (albumin and alpha 2HS-glycoprotein) proteins in rat bone. J Bone Miner Res. 1993;8:485–496. [PubMed]
45. Nilsson SK, Johnston HM, Whitty GA, et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood. 2005;106:1232–1239. [PubMed]
46. Schmits R, Filmus J, Gerwin N, et al. CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity. Blood. 1997;90:2217–2233. [PubMed]
47. Scott LM, Priestley GV, Papayannopoulou T. Deletion of alpha4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol Cell Biol. 2003;23:9349–9360. [PMC free article] [PubMed]
48. Stier S, Ko Y, Forkert R, et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med. 2005;201:1781–1791. [PMC free article] [PubMed]
49. Wang MW, Consoli U, Lane CM, et al. Rescue from apoptosis in early (CD34-selected) versus late (non-CD34-selected) human hematopoietic cells by very late antigen 4- and vascular cell adhesion molecule (VCAM) 1-dependent adhesion to bone marrow stromal cells. Cell Growth Differ. 1998;9:105–112. [PubMed]
50. Yamaguchi M, Ikebuchi K, Hirayama F, et al. Different adhesive characteristics and VLA-4 expression of CD34(+) progenitors in G0/G1 versus S+G2/M phases of the cell cycle. Blood. 1998;92:842–848. [PubMed]
51•. Dao MA, Nolta JA. Cytokine and integrin stimulation synergize to promote higher levels of GATA-2, c-myb, and CD34 protein in primary human hematopoietic progenitors from bone marrow. Blood. 2007;109:2373–2379. [PMC free article] [PubMed]
Binding of human CD34+ bone marrow cells to fibronectin in vitro in addition to specific cytokines results in upregulation of GATA-2, c-myb as well as CD34 total protein but not cell surface expression. These genes have previously been shown to maintain hematopoietic progenitor quiescence.
52•. Gottschling S, Saffrich R, Seckinger A, et al. Human mesenchymal stromal cells regulate initial self-renewing divisions of hematopoietic progenitor cells by a beta1-integrin-dependent mechanism. Stem Cells. 2007;25:798–806. [PubMed]
β1-Integrins are shown to be critical in regulating self-renewal of human hematopoietic progenitor cells verifying what has been shown in animal models.
53. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149–161. [PubMed]
54. Wilson A, Murphy MJ, Oskarsson T, et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004;18:2747–2763. [PMC free article] [PubMed]
55••. Haug JS, He XC, Grindley JC, et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell. 2008;2:367–379. [PubMed]
N-CAD expression levels were shown to vary among bone marrow cells between low, intermediate and high. The greatest reconstitution potential from freshly isolated HSCs is contained in the N-CAD low population though if cultured overnight the reconstitution potential of N-CAD intermediate is greatly improved.
56••. Kiel MJ, Radice GL, Morrison SJ. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell. 2007;1:204–217. [PubMed]
In this study, all of the cells displaying HSC activity in irradiated mice are contained in the N-cadherin negative population of bone marrow cells. They were also unable to detect N-cadherin by PCR, or Western blotting in cells purified in HSCs.
57••. Jung Y, Wang J, Song J, et al. Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood. 2007;110:82–90. [PMC free article] [PubMed]
The authors show through genetic manipulation that Anxa2-deficient animals have fewer HSCs in the marrow and that osteoblasts derived from these animals show much reduced adhesion to HSCs. Further they show that inhibition of Anxa2 binding in irradiated mice after a whole marrow transplant reduces HSC engraftment and ultimately survival of the animals.
58. Hsu HC, Ema H, Osawa M, et al. Hematopoietic stem cells express Tie-2 receptor in the murine fetal liver. Blood. 2000;96:3757–3762. [PubMed]
59. Puri MC, Bernstein A. Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci U S A. 2003;100:12753–12758. [PMC free article] [PubMed]
60. Arai F, Ohneda O, Miyamoto T, et al. Mesenchymal stem cells in perichondrium express activated leukocyte cell adhesion molecule and participate in bone marrow formation. J Exp Med. 2002;195:1549–1563. [PMC free article] [PubMed]
61. Arai F, Hirao A, Suda T. Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc Med. 2005;15:75–79. [PubMed]
62. Ponomaryov T, Peled A, Petit I, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000;106:1331–1339. [PMC free article] [PubMed]
63. Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201:1307–1318. [PMC free article] [PubMed]
64. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–637. [PMC free article] [PubMed]
65. Larochelle A, Krouse A, Metzger M, et al. AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates. Blood. 2006;107:3772–3778. [PMC free article] [PubMed]
66. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977–988. [PubMed]
67. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845–848. [PubMed]
68. Jung Y, Wang J, Schneider A, et al. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone. 2006;38:497–508. [PubMed]
69. Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998;95:9448–9453. [PMC free article] [PubMed]
70. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998;393:595–599. [PubMed]
71•. Rossi L, Manfredini R, Bertolini F, et al. The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration. Blood. 2007;109:533–542. [PubMed]
In-vitro UTP increases stem cell migration and cell adhesion mediated by fibronectin. In-vivo results show that pretreating bone marrow cells with UTP improves the homing of human CD34+ cells in immune-deficient mice.
72•. Sierro F, Biben C, Martinez-Munoz L, et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci U S A. 2007;104:14759–14764. [PMC free article] [PubMed]
Conditional knockouts of CXCR7 in mice show no hematopoietic defects in contrast to CXCR4 and CXCL12 knockouts. CXCR7 is shown to form heterodimers with CXCR4 and enhance CXCL12 signaling but is not an essential component.
73. Rodan SB, Rodan GA, Simmons HA, et al. Bone resorptive factor produced by osteosarcoma cells with osteoblastic features is PGE2. Biochem Biophys Res Commun. 1981;102:1358–1365. [PubMed]
74••. North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447:1007–1011. [PMC free article] [PubMed]
Treatment of zebrafish with chemicals known to stimulate PGE2 production subsequently increased HSCs. Coinciding with the zebrafish data are data in mice showing ex-vivo treatment of murine bone marrow increased spleen colony formation in subsequent transplants by three-fold at 12 days after transplantation.
75. Tetradis S, Pilbeam CC, Liu Y, et al. Parathyroid hormone increases prostaglandin G/H synthase-2 transcription by a cyclic adenosine 3′,5′-monophosphate-mediated pathway in murine osteoblastic MC3T3-E1 cells. Endocrinology. 1997;138:3594–3600. [PubMed]
76. Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423:409–414. [PubMed]
77. Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–452. [PubMed]
78. Murdoch B, Chadwick K, Martin M, et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci U S A. 2003;100:3422–3427. [PMC free article] [PubMed]
79. Zhou H, Mak W, Zheng Y, et al. Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J Biol Chem. 2008;283:1936–1945. [PubMed]
80••. Fleming HE, Janzen V, Lo Celso C, et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008;2:274–283. [PMC free article] [PubMed]
In this study, authors used an osteoblast-specific promoter to drive the over-expression of Dkk1 a Wnt inhibitor. Wnt signaling was impaired in HSCs and resulted in HSCs cell cycling and impaired regeneration after transplantation, demonstrating microenvironmental control of HSCs proliferation.
81•. Nemeth MJ, Topol L, Anderson SM, et al. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl Acad Sci U S A. 2007;104:15436–15441. [PMC free article] [PubMed]
Wnt5a inhibits canonical Wnt signaling by destabilizing β-catenin. This results in decreased proliferation in HSCs as well as increased short-term repopulation due to a pool of quiescent stem cells after Wnt5a treatment.
82. Adams GB, Chabner KT, Alley IR, et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 2006;439:599–603. [PubMed]
83. Silver IA, Murrills RJ, Etherington DJ. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res. 1988;175:266–276. [PubMed]
84••. Walkley CR, Shea JM, Sims NA, et al. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell. 2007;129:1081–1095. [PMC free article] [PubMed]
The authors demonstrated that loss of retinoblastoma in either the microenvironment or in HSCs alone is insufficient to disrupt hematopoiesis. However, loss of retinoblastoma in both the microenvironment and HSCs causes severe myeloproliferation and loss of HSCs from the marrow.
85••. Walkley CR, Olsen GH, Dworkin S, et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007;129:1097–1110. [PMC free article] [PubMed]
The study showed that wild type bone marrow transplanted into RARγ-deficient mice resulted in a myeloproliferative syndrome mediated entirely by the RARγ-deficient microenvironment.
86. Zhang Z, Vuori K, Reed JC, Ruoslahti E. The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci U S A. 1995;92:6161–6165. [PMC free article] [PubMed]
87. Damiano JS, Cress AE, Hazlehurst LA, et al. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood. 1999;93:1658–1667. [PubMed]
88. Hazlehurst LA, Argilagos RF, Emmons M, et al. Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells. Cancer Res. 2006;66:2338–2345. [PubMed]
89. Hazlehurst LA, Damiano JS, Buyuksal I, et al. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR) Oncogene. 2000;19:4319–4327. [PubMed]
90•. Hazlehurst LA, Enkemann SA, Beam CA, et al. Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res. 2003;63:7900–7906. [PubMed]
91. Tabe Y, Jin L, Tsutsumi-Ishii Y, et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res. 2007;67:684–694. [PubMed]
Integrin-linked kinase is activated by binding of β-integrins, expressed by leukemic cells, to bone marrow stromal cells activating the Akt pathway. Further inhibitors of the Akt pathway result in increased apoptosis in leukemia cells.
92. Mohle R, Bautz F, Rafii S, et al. The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood. 1998;91:4523–4530. [PubMed]
93. Mohle R, Schittenhelm M, Failenschmid C, et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol. 2000;110:563–572. [PubMed]
94••. Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25:1315–1321. [PubMed]
Primitive CD34+ human AML cells were shown to home to the endosteum of nonobese diabetic-severe combined immunodeficiency (NOD/SCID)/IL2rynull mice. Further AML cells engrafted within the endosteum were resistant to chemotherapy-induced apoptosis.
95••. Zhao C, Blum J, Chen A, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528–541. [PMC free article] [PubMed]
A conditional knockout of β-catenin in the hematopoietic system resulted in deficient self-renewal in both normal and leukemic stem cells. This defect impaired the development of CML in a BCR and ABL leukemogenesis model.
96•. Guo W, Lasky JL, Chang CJ, et al. Multigenetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature. 2008;453:529–533. [PMC free article] [PubMed]
Conditionally knocking out PTEN in the mouse hematopoietic system results in a myeloproliferative disorder and eventually leads to acute T lymphoblastic leukemia (T-ALL). Further, the deletion of just one allele of β-catenin results in reduced incidence and delayed onset of T-ALL in the PTEN null model indicating that β-catenin may play a role in the development of LSC.
97. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441:475–482. [PubMed]
98. Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006;441:518–522. [PubMed]
99. Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–1174. [PubMed]
100•. Matsunaga T, Fukai F, Miura S, et al. Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia. 2008;22:353–360. [PubMed]
Primary leukemia cells with high expression of α4-integrins display resistance to the chemotherapeutic Ara C when adhered to fibronectin. Leukemia samples with low α4-integrin expression show little resistance to Ara C treatment. Disruption of fibronectin binding with the peptide FNIII14 resulted in sensitization of the leukemia samples to Ara C treatment and in a mouse model of minimal residual disease increased survival to 100%.
101•. Zhao Y, Bachelier R, Treilleux I, et al. Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res. 2007;67:5821–5830. [PubMed]
αvβ3 Integrin is expressed by breast cancer cells that preferentially metastasize to bone where they induce osteoclastic-mediated bone resorption. Treatment with an antagonist of αvβ3 integrin results in a decrease in bone resorption and skeletal tumor burden.
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links