Stem cells modulate tissue formation, maintenance and repair based on a complex interaction of cell-autonomous and cell-nonautonomous regu-latory mechanisms. Reductionist approaches to elucidating the intrinsic regulators of stem cell physiology have been extremely productive and have identified many of the molecules involved. However, understanding the extrinsic regulation of these key molecules will ultimately require the definition of the complex microenvironments in which the stem cells self-renew, differentiate or undergo apoptosis.

Where adult stem cells reside has only become available for study as functional definitions of stem cells have improved. Ironically, the hematopoietic stem cell (HSC) is well characterized by ‘immunophe-notype’, yet its precise location in bone marrow has been refractory to study mainly because this most liquid of tissues resides in the most rigid, bone. In contrast, stem cell populations in other tissue types have more fixed architectural positions yet have been relatively resistant to definition partly because of their anatomical relationships. These cells are embedded in tissues and therefore cannot be readily transplanted, a key element in defining stem cell function. Identifying these cell types, then, is based mostly on lineage-tracing studies and the ability of the cells to retain dyes that are diluted with cell division. In contrast to their more vigorously proliferative daughter cells, stem cells reside in rela-tive quiescence, dividing infrequently and therefore retaining dye. The positions of stem cells of the intestine, skin and brain are therefore now characterized in location. However, insights into the regulatory func-tions of local cell types in the niche have been driven mainly by studies of invertebrate systems.

Studies of gonadal tissue from Drosophila melanogaster and Caenorhabditis elegans have permitted the definition and identification of ancillary niche cells, physical cell-cell interactions and the molecular

The hematopoietic stem cell in its placeGregor B Adams & David T Scadden

A signature characteristic of stem cells is their ability to self-renew, affording a theoretically limitless ability to produce daughter cells and their descendents. This near-timeless dimension of stem cell function is not free of the constraints of place. The idea that highly specialized ‘microenvironmental’ cues participate in the regulation of stem cells has evidence in classic embryology and more recently in adult stem cells through the use of model organisms. There is now ample evidence that an anatomically defined, specifically constituted place represents the niche for hematopoietic and other tissue-specific stem cells. This review provides a conceptual framework and detailed account of the hematopoietic stem cell niche as defined at present. The components are assembling into a more complex view of the niche and may now be amenable to examination as a system and possibly to alteration to affect outcomes in immune regeneration.

pathways that govern the interaction between the stem cell and its local environment1–3. The work of several researchers studying these inver-tebrate systems has provided in-depth experimental evidence for a spe-cialized environment for stem cells that was first proposed in the setting of hematology in 1978 (ref. 4). The ideas derived from invertebrates are along several lines and serve as guides of relevance to ‘immunohematol-ogy’: first, the number of stem cells in a niche is tightly regulated; second, physical interaction among heterologous types of cells is important for the maintenance of the stem cell state; third, products of the niche provide the molecular basis for physical interactions and a balance of inhibitory and stimulatory signals governing stem cell number and function; fourth, niche occupancy can impose ‘stem cell–like’ characteristics on some cells even if they are not stem cells. Each of these is discussed below.

Stem cells represent a peculiarly troublesome cell type. They are essen-tial for the formation, maintenance and repair of tissues, yet they func-tion simply as a root source of more mature ‘offspring’ that do the real business of tissue function. Stem cells also represent a potential threat to the organism, as they have such undifferentiated characteristics, have self-renewal capabilities and can produce offspring with explosive prolif-erative capability. Stem cells out of balance could certainly pose a danger to survival of the organism and, at the very least, in large numbers pose a substantial energy drain. The idea that stem cell numbers are highly constrained is perhaps best demonstrated in the D. melanogaster ger-marium, in which germline stem cells are generally restricted to two to three cells and only rarely exceed that number5. In mammalian systems, HSCs have been estimated to be conserved in number even between animals of very different sizes6. Estimates of total HSCs in animals as disparate as the mouse and cat are 1.1 × 104 cells per animal for each species. Thus, the stem cell pool size is a governed parameter and any efforts at expansion in vivo will probably have only modest success. The levels of control for this parameter are probably many, and understand-ing them will be important for the ultimate development of stem cell manipulation strategies.

One such level of control may be the apparent requirement for physi-cal interaction between stem cells and their niche. In invertebrates, this has again been well demonstrated. Disruption of the cadherin-mediated connection between D. melanogaster female germ cell stem cells and the

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SPEC IAL I ZED IMMUNOLOG ICAL N ICHES R E V I E W

Center for Regenerative Medicine, Massachusetts General Hospital,

Harvard Medical School, Boston, Massachusetts 02114, USA, and Harvard

Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138,

USA. Correspondence should be addressed to D.T.S.

(scadden.david@mgh.harvard.edu).

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niche ‘cap’ cell results in stem cell loss7. Whether that dependence is truly due to maintenance of the junction or simply to proximity to niche cell products is not entirely clear. However, a requirement for physical inter-action with niche cells would be one effective means of limiting stem cell numbers. It would also provide an orienting stimulus affecting cell polarity that may be critical in determining the outcome of cell division. For example, the relative balance between symmetric and asymmetric cell division can greatly influence stem cell numbers and the ability of stem cells to produce maturing daughter cells. A cell that divides with a cleavage plane perpendicular to niche cell has the potential to have both daughter cells remain in contact with the niche cell. In contrast, a cleavage plane parallel to the niche cell would result in one daughter cell at a distance from the niche cell. These distinct localizing features may be envisioned as resulting in either two niche-bound stem cells (sym-metric cell division) or one daughter cell at a distance from the niche, enabling a differentiation program, while the other remains at the niche (asymmetric division yielding one maturing cell and one stem cell). Such polar organization now has empiric support in D. melanogaster, in which changing the stem cell cleavage orientation by modifying the adeno-matous polyposis coli tumor suppressor protein considerably alters the number of stem cells8. Whether the same is true for mammalian systems has not been well defined, but it is now apparent that N-cadherin is pres-ent at the interface of some stem cells and niche cells9,10.

Other regulatory dimensions of the niche are still being explored, but molecular interactions in one system often provide insight into another. Detailed analyses of male and female D. melanogaster gonads initially demonstrated distinct signaling pathways. A Janus kinase–signal trans-ducer and activator of transcription (Jak–STAT) pathway identified as crucial for male germ stem cell regulation was thought to be distinctive to the male and not present in the ovary. However, data now indicate otherwise; there are common Jak–STAT signaling pathways in both germ stem cells11. Similarly, Notch pathway activation is important in main-taining germ stem cells in C. elegans and has also been linked to the HSC niche in mice12,13. Therefore, the rules, pathways and perhaps structural components of invertebrate stem cell niches may provide opportunities for accelerating the exploration and understanding of how the special-ized microenvironment can affect mammalian stem cells.

Finally, the invertebrate system offers one note of caution that must be explored in mammalian niches. Niche structures have the potential to determine stem cell state and not just be supportive. For example, studies have shown that a vacant niche can remain viable and that other cell types may engage the niche, with a resultant change in phe-notype. Depending on the specific system, it seems that non–stem cells can acquire either a more proliferative phenotype or frankly revert to a stem cell–like, less differentiated state14,15. That finding or idea raises the ‘power’ of the niche to another plane, suggesting that it may participate actively in imposing stem cell–like characteristics even on ectopic cells of different phenotype. An intriguing possibility is then posed: if the same holds true in mammals, the niche may be capable of contributing to abnormal tissue regulation, possibly ‘encouraging’ aberrant or malignant cells by providing ‘stem-like’ features to a more mature cell type.

HSC interactions with specialized microenvironmentsIn the mammalian organism, one of the most extensively studied stem cells is that of the hematopoietic system. In mice, HSCs first arise in the yolk sac and produce embryonic hemoglobin containing red blood cells at embryonic day 7 (E7), followed by a second wave of erythromyeloid cell production from the yolk sac at E8.25 (ref. 16). In the embryo proper of the mouse, the aorto-gonadal-mesonephros and placental regions of the developing embryo begin production of definitive hematopoietic cells at around E10.5 (refs. 17,18). The liver is then ‘invested’ with stem cells to become the main source of hematopoiesis until approximately the second trimester, when the HSCs are thought to translocate via the peripheral circulation to the bone cavities to form the bone marrow. The peripatetic developmental history of HSCs does not stop with arrival in the marrow space. Instead, it seems that these cells undergo regular trafficking into and out of the bone, spending brief intervals in the circu-lation. In mice whose peripheral circulation is joined, it has been shown that HSC residence time in the circulation is less than 6 seconds for more than 99% of the cells19. As approximately 100–400 cells are present in the circulation at a given time, many stem cells transit through the circula-tion daily. It is not apparent that they all necessarily encounter a specific niche along the way or that those circulating are the same as those that spend time in the bone marrow. These caveats notwithstanding, it is reasonable to conclude that stem cells, although regulated by place, are not static in a given space. They seem to be in motion, and imaging of primitive cells ex vivo has indicated that indeed they have highly dynamic membrane extensions and rapid motility20. Although mature cells of the immune system may be viewed as using motility as a needed feature of surveillance in host defense, it is less teleologically intuitive to under-stand these phenomena in stem cells. Is there some monitoring function they provide? It is not at all apparent, although bone marrow–derived cells do incorporate into neovascular sites, suggesting that some involve-ment in repair at a distance is possible21. This frequent trafficking is a process that is presumably recapitulated in kind during the intravenous delivery of stem cells during transplantation therapy. Cells moving on and off niche sites may the basis for the engraftment of infused stem cells that can occur with low frequency even without cytotoxic ‘empty-ing’ of the niche22.

The movement of HSCs to bone marrow occurs early in bone for-mation. The cartilaginous anlage of bone initially becomes infiltrated by vessels and, with them, cartilage-consuming phagocytic cells called chondroclasts. Osteoblasts arrive, but the arrival of HSCs occurs only after mineralization of extracellular matrix laid down by osteoblasts is initiated. This combined presence of osteoblasts and mineral in the developing bone at the time hematopoiesis shifts to bone marrow suggests the many components of bone contributing to bone marrow regulation that have since been demonstrated.

Figure 1 Interactions in the endosteal niche. Hematopoietic stem cells engage niche components (large font) through interactions that modulate their function. For the molecular components of the niche–stem cell interactions, black indicates definitive involvement and gray indicates putative involvement. KL, Kit ligand; Dkk1, Dickkopf1; Wnt, wingless; Hh, hedgehog; TFG-BMP, transforming growth factor-β family and bone morphogenic protein family; LRP5-LRP6, lipoprotein related–receptor proteins 5 and 6; TGFR-BMPR, transforming growth factor receptor and bone morphogenic protein receptor; VLA, very late antigen (integrin).

OsteoblastStem cell

Ca++

N-cadherinJagged1Angiopoietin-1CXCL12KLDkk1WntHhTGF-BMP

Osteopontin CD44VLA-4VLA-5

Ca2+

CaR

Osteoblast Stem cellN-cadherinNotch1Tie-2CXCR4KitFrizzled–LRP5,6–LRP6PatchedTGFR-BMPR

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Although bone marrow has been a recognized site of blood cell pro-duction for decades, what bone does for bone marrow has been less clear. Simple bone marrow histology demonstrated an admixture of differentiating hematopoietic cells in spaces bounded by trabecular bone, endothelium-lined sinuses, feeder vessels and adipocytes. Regional clustering in grape-like arrangement of red cell precursors, in particular at the trabecular interface, suggests a more complex anatomic organi-zation. However, studies of primitive cells labeled ex vivo and tracked in vivo have demonstrated the endosteal localization of HSCs23. Those studies, coupled with in vitro coculture studies indicating the ability of osteoblastic cells to secrete cytokines and support primitive blood cells ex vivo, have set the stage for more focused analysis of the interaction between bone and bone marrow24,25.

What bone does for bone marrowDistinguishing bone from other mesenchymal tissues are several key features: a unique mesenchymal cell type (the osteoblast), distinctive extracellular matrix glycoproteins and a uniquely rich mineral con-tent of high density calcium salts. Each of these components has now been shown to participate in a regulatory microenvironment for HSCs. In aggregate cells, matrix and mineral contribute to a unique microenvironment or niche.

Three main lines of evidence have indicated involvement of the osteo-blast. The first two were concurrent studies examining genetic models that modified osteoblasts, showing that they secondarily affect HSCs. One group, studying bone morphogenetic protein signaling, created a conditional knockout of the bone morphogenetic protein 1a receptor that caused a bony defect, increasing the number of osteoblasts9. HSC numbers were proportionately increased and were found to be localized in immediate proximity to spindle-shaped osteoblasts, forming what seemed to be a homotypic junction associated with N-cadherin. Taking a different tack, the second group targeted the osteoblast specifically using a transgenic mouse with a constitutively active parathyroid hormone receptor driven by the osteoblast-specific 2.3-kilobase fragment of the promoter of the gene encoding procollagen, type I, α1. The resulting mouse had increased trabecular bone and increased numbers of HSCs13. The increase in primitive cell support was associated with increased expression of the Notch ligand Jagged1, and increased Notch1 activation that could be blocked by γ-secretase inhibition, suggesting involvement of that pathway in the ‘upmodulation’ of stem cells with osteoblast stim-ulation. Jagged1-deficient mice have normal hematopoiesis, so the effect may be obtained only with osteoblast stimulation and may not partici-pate in homeostatic regulation of stem cells at the endosteal niche26. The third piece of evidence for involvement of the osteoblast has been provided by a study with selective depletion of osteoblasts in vivo due to a transgene construct of the gene encoding herpes simplex virus thy-midine kinase under the control of an osteoblast-specific promoter27. Exposure of the mice to ganciclovir, because of expression of the herpes simplex virus thymidine kinase cassette, selectively induces metabolic death of osteoblasts and a subsequent decrease in hematopoietic capac-ity. Therefore, the osteoblast is a cell participant in the stem cell niche providing regulatory cues for the maintenance of hematopoiesis.

Although the osteoblast is a cellular component of the niche, the prod-ucts of the osteoblast that participate in the regulatory microenvironment for stem cells are known in only limited detail. Interaction of angiopoietin 1 at the osteoblast surface with Tie-2 on stem cells is important for main-taining stem cell quiescence in the niche10 (Fig. 1). Those data have identi-fied a set of molecular interactions in the niche that are probably just the beginning of a host of previously underappreciated pathways creating a synaptic-like interface. Candidates being studied are those of the wing-less, hedgehog, bone-morphogenetic protein, Kit ligand and chemokine

stromal cell–derived factor 1 (also called CXCL12) pathways (Fig. 1), but those are based on candidate gene approaches, and more global analyses will probably yield many others not predicted at present. Unanticipated interactions are perhaps best exemplified by the identification of involve-ment of adrenergic signaling in altering osteoblast function, reducing CXCL12 production and thereby leading to stem cell release into the circulation28. The demonstration that adrenergic signaling may alter the niche raises another important issue.

The interface of the osteoblast and stem cell is probably rich in molecular interactions that guide the response of stem cells to specific physiological conditions. The niche may be the focal point for changes in the state of tissues that result in a change in the regenerative processes rooted in stem cell activity. Exactly how the niche integrates signals of tissue state is unclear, but neural input does seem to be one possibility, as does systemic cytokine or hormone activity13,28,29. Divergent pro-cesses may come to bear on the niche–stem cell interface. One study has shown that intra–stem cell changes in c-Myc concentrations alter molecular interactions at the niche, including N-cadherin expression, and are associated with aberrant accumulation of stem cells30. A per-turbation in the regulation of stem cell number and function at the level of molecular interactions in the niche might participate in the pathophysiology of bone marrow failure or hyperproliferation states. Conversely, these interactions may offer a therapeutic opportunity to manipulate stem cells.

In addition to the mesenchymal cell types that distinguish bone, it also has a unique mix of extracellular matrix components. Osteopontin has been studied particularly closely because of its known involvement in other hematological settings. In particular, osteopontin is important in mature immune cell function, serving as a mediator of T helper type 1 and 2 ‘choice’, cell growth and localization. Osteopontin is useful for assessing in bone marrow function in part because of its cytokine and adhesion characteristics in those other settings, but also because it is a modulated product of osteoblasts and binds to cell surface receptors on HSCs, CD44 and the α4 and α5β1 integrins31 (Fig. 1). Two studies have used osteopontin-null mice to demonstrate that there is a stem cell–non-autonomous function for osteopontin in regulating stem cells in the niche32,33. Notably, an absence of osteopontin results in an increase in the number of HSCs, by a stem cell–nonautonomous or microenviron-ment-dependent mechanism. Those studies have shown not only that many factors, including apoptosis and cell cycling, may contribute to the increase in stem cell number but also that when activated osteoblasts are in the niche and osteopontin is not, the population expansion of stem cells is ‘superphysiological’. Thus, osteopontin may be a constraining factor on stem cell number and perhaps may restrict the number of stem cells that can result from niche activation.

The mineral content of bone is an obviously distinctive characteristic distinguishing it from other mesenchymal tissues. Classic physiological experiments have measured quantities of ionic calcium in tissues and have defined that although the Ca2+ concentration is generally rigidly maintained in most extracellular spaces, at sites of injury or inflamma-tion and at the surface of remodeling bone, the concentration can vary upward by more than an order of magnitude34. It is then reasonable to question whether this simple ionic gradient could provide the basis for hematopoiesis in mineralized tissue. Extracellular Ca2+ concentrations are recognized by the seven-transmembrane calcium-sensing receptor and can result in an intracellular G protein–coupled response35. That receptor is on hematopoietic cells and has been identified on the surface of HSCs36. In mice deficient in that receptor, HSCs form normally in the fetal liver but do not engraft in the bone marrow. Hematopoiesis in sites such as the spleen (important in mouse but not in normal adult human hematopoiesis) occurs, but the cells are unable to engage the endosteal sur-

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face of bone or to successfully engraft in bone marrow. The effect is stem cell autonomous, and transplantation into wild-type mice with normal calcium homeostasis does not alter the phenotype. Therefore, the ability of stem cells to sense and respond to the increased calcium concentrations at the endosteal surface participates in creating the unique stem cell-niche interaction that enables bone marrow hematopoiesis.

Multiple niches for the HSCThe finding that HSCs without the calcium-sensing receptor can engraft in extramedullary spaces and foster blood cell production strongly sug-gests that regions other than the endosteal surface can function as a stem cell niche, at least in the mouse. Similar conclusions might be drawn from studies of mice with bony defects in which either an osteopetrotic or defective bony phenotype is associated with extramedullary hema-topoiesis. For example, Runx2 is an osteoblast-associated transcription factor without which ossified bone does not form37. Yet hematopoiesis continues even after the developmental shift to bone marrow would normally occur. Cell production is abnormal, but hematopoiesis is ongoing. Similarly, a mouse with osteopetrosis due to deficiency in the macrophage-colony stimulating factor receptor has altered hematopoi-esis with extramedullary sites involved38. One site known to support hematopoiesis in mice and in certain disease conditions in humans is the spleen. This richly vascularized tissue is still relatively unexplored territory in terms of specific niche definition. In contrast, perivascular tissue in bone marrow now seems to be a potential niche site.

Label retention is a mode of imaging stem cells that has been applied to hematopoietic as well as nonhematopoietic tissues. With that strat-egy, the endosteal surface has been identified histologically as a site for quiescent stem cell localization9. The alternative of antigen labeling was not successful on histological sections until the identification of the labeling of long-term repopulating HSCs by members of the sig-naling lymphocyte activation molecule family (specifically CD150)39. Immunohistochemistry has been used to find CD150+ cells in close proximity to the endothelially lined vascular tissue, a site that has been noted as a regulatory zone for megakaryocyte progenitors40. The CD150+ HSCs were notably more abundant in this area than at the endosteal zone, where only approximately 14% of labeled cells could be found. The one caveat to those studies is that where cells reside may not be equiva-lent to a functional niche. The perivascular space has been hypothesized as being a site where more mitotically active stem cells may be located, and perhaps that is why it has not been identified in label-retaining assays in bone marrow. However, whether the perivascular region is simply a ‘way station’ en route to intravascular trafficking, a repository for stem cells or a true regulatory niche remains to be determined.

Other data analyzing the bone marrow microvasculature from a dif-ferent perspective, however, have provided some support for the idea of a perivascular niche. In experiments attempting to elucidate the mecha-nisms for localizing primitive populations of cells in bone marrow, hematopoietic tumor cell lines have been used in conjunction with high-resolution video confocal microscopy41. Those data have shown that cells in the circulation home to specific regions of microvessels and traffic into the perivascular space. The homing site has been characterized by regional expression of the chemokine CXCL12, and homing to those microdo-mains is blocked by downregulation or pharmacological blocking of the CXCL12 receptor CXCR4. Those same zones are used by primitive pri-mary hematopoietic cells and are the site where cells labeled ex vivo were found to be resident for at least 60 days, retaining label. Those data do not conclusively demonstrate that the perivascular region is a regulatory stem cell niche; however, they are consistent with the idea that primitive cells not only localize to the perivascular space but also undergo slow cell division. Therefore, there may be highly specialized microvascular as well as osteo-

blastic niches in the bone marrow that participate in hematopoiesis. The distinctions between these sites is probably important functionally, but can only be hypothesized at this time. Ultimately, it will be highly infor-mative to image HSCs and thereby determine if they move between the perivascular or endosteal sites or if these represent distinctive homes for different subset of cells. It will be useful to determine which population is mobilized in strategies used clinically to get stem cells into the circulation. Finally, it will also be useful to determine whether in settings of disease these niches have different functions; specifically, whether neoplastic cells have different responsiveness to one niche versus another.

Niche modelingAs the niche is an idea with increasing dimension as parts are defined, the potential to exploit that information therapeutically is coming into focus. There may be several ways in which that may occur. Perhaps the individual components function only in the context of an integrated sys-tem, but are studied alone. As distinct parts are identified, the potential to reorganize them ex vivo to enable more controlled, in-depth analysis of the system may become possible. This could be envisioned as including several lines of enquiry, such as examination of the physical relationships needed in the niche, direct measurement of symmetric versus asym-metric division in the niche and the potential to do ‘chemical screening’ to alter the niche. Furthermore, the niche components begin to be seen as potential contributors to states of stem cell dysfunction. That could happen in the setting of acquired marrow failure or in dysplastic and neoplastic states. It is now becoming possible to examine whether the normal stem cell niche is similar to that of the leukemic stem cell, for example. Does altering the niche change the relative support of normal versus abnormal stem cells? Can the niche become a target that can be manipulated to change the balance of competition in the marrow that accompanies diseases such as leukemia and myelodysplasia?

Recognition of the niche components affords the possibility of target-ing those components to affect stem cell function in settings of clinical relevance. In particular, the identification of the osteoblast as a niche participant suggests that agents developed to target the osteoblast in context of bone disorders such as osteoporosis may be re-examined as possible modifiers of HSC physiology. One example of this is a mouse bone marrow transplant model in which the recipients are treated with parathyroid hormone to affect osteoblast number and function13. The resulting increase in stem cells in homeostatic conditions is only twofold. However, in conditions of stress, in which irradiated murine recipi-ents are transplanted with limiting numbers of stem cells, stimulating the recipient with parathyroid hormone injections generates greatly improved survival statistics and much increased bone marrow cellular-ity. Whether using parathyroid hormone to improve transplant outcome can be recapitulated in human patients is unclear, but at least one mul-ticenter clinical study has been initiated based on those data. Therefore, knowledge of the niche may be relevant for modifying stem cell out-comes clinically. Knowing stem cells in their place may help stem cells achieve a more prominent position in the clinical armamentarium.

ACKNOWLEDGMENTSWe thank C. Shambaugh for administrative assistance. Supported in part by the National Institutes of Health (HL081030 and HL44851), the Burroughs Wellcome Fund and the Leukemia & Lymphoma Society.

COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Immunology

website for details).

Published online at http://www.nature.com/natureimmunology/Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/

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