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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000055
HEMATOPOIESIS: Edited by Hal E. Broxmeyer

Bone marrow localization and functional properties of human hematopoietic stem cells

Boyd, Allison L.a,b; Bhatia, Mickiea,b

Free Access
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Author Information

aStem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada

bDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

Correspondence to Mickie Bhatia, McMaster Stem Cell and Cancer Research Institute (SCC-RI), Michael G. DeGroote School of Medicine, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON, Canada L8S 4K1. Tel: +1 905 525 9140x28687; e-mail: mbhatia@mcmaster.ca

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Abstract

Purpose of review

Historically, studies of the hematopoietic stem cell (HSC) microenvironment in bone marrow have focused on the identification of individual supportive cell lineages likely to be responsible for maintaining HSCs in a self-renewing and regenerative state. More recently, awareness has developed regarding the broad and dynamic heterogeneity of nonhematopoietic cells that reside within the bone marrow space. We review recent insights that provide an emerging and complex context for understanding the spatially dependent regulation of HSC functional properties in the bone marrow and the collective inputs of multiple cell types.

Recent findings

Within the last 18 months, high-resolution imaging, xenograft modeling, and genetic mouse models have afforded innovative methods of detecting and interrogating HSCs with precision at the cellular level. Spatially distinct sites within the bone marrow house functionally divergent HSCs and progenitors, and these different habitats are becoming carefully characterized from a cellular and molecular perspective. This is critical toward understanding how bone marrow microenvironments adapt to accommodate cellular demands for hematopoiesis and how these mechanisms are disrupted in pathological conditions.

Summary

The bone marrow is not a continuum but an integrated unit with complex trophic interactions. Emphasis on human data will become necessary as these concepts mature and develop translationally toward changing clinical practices in HSC transplantation and even in the treatment of leukemias.

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INTRODUCTION

Bone marrow-resident hematopoietic stem cells (HSCs) are responsible for sustainable blood cell production throughout life. This is achieved by balancing between states of self-renewal and differentiation according to changing demands for circulating immune cells and erythrocytes. The mechanisms that either maintain self-renewing HSCs or direct their differentiation are largely cell extrinsic in nature, and evidenced by the loss of functional HSC capacity that accompanies prolonged ex-vivo culture [1,2]. In-vitro culture systems fail to recapitulate the cellular and molecular complexity of the bone marrow microenvironment, and despite innovations to achieve more physiologically relevant culture conditions [3,4▪], functional interrogation of HSCs remains limited in this context. In-vivo experimental modeling employing genetic models, in-situ high-resolution microscopy, and sophisticated transplantation experiments have proven to be invaluable toward the identification of key specialized elements contributing to long-term HSC preservation [5▪]. These techniques, together with complementary translational efforts [6▪▪,7▪], are beginning to provide a comprehensive and integrated understanding of HSC niche regulation that will better inform the therapeutic management of HSCs under states of injury and disease.

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CELLULAR AND ARCHITECTURAL COMPOSITION OF THE HEMATOPOIETIC STEM CELL MICROENVIROMENT

Since the early theoretical and experimental [8,9] evidence supporting the existence of HSC-specific niches in the bone marrow, concentrated efforts systematically evaluated the HSC-supportive capacities of the bone marrow-resident cell types on an individual lineage basis. Such studies, informed mostly by promoter-driven cell ablation techniques and static in-situ microscopy, included the consideration of osteoblasts [8,9], endothelial cells [10], osteoclasts [11], other bone marrow-resident macrophages [12], megakaryocytes [13▪], nonmyelinating Schwann cells [14], T-regulatory cells [15], adipocytes [16], and mesenchymal stem cells (MSCs) [17]. Of these cell types, osteoblasts and endothelial cells initially emerged as promising candidates that attracted the most attention as fundamental HSC regulators. In this context, endosteal and vascular bone marrow regions were often juxtaposed as mutually exclusive territories, largely based on the premise that the endosteum offers a hypoxic microenvironment, and, therefore, must be poorly perfused [18]. Current understanding, however, favors a more integrated view between vasculature and the endosteum. Endothelial cells have been reported to situate in close association with osteoblasts in both the calvarium [19] and the long bones [20,21,22▪▪,23▪,24], with suggestions that highly trabeculated areas may even be more vascularized than central bone marrow cavities [22▪▪,24]. Furthermore, recent insights propose that the hypoxic profile characteristic of bone marrow-localized HSCs is independent of their cell cycle status, and could instead reflect cell-intrinsic metabolic properties, with little evidence of significant oxygen tension gradients within the bone marrow [23▪].  

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More recently, important interactions between HSCs and functionally primitive MSCs have been described within the bone marrow [17]. However, it remains to be resolved whether MSCs unilaterally influence HSCs, or whether these two cell types are reciprocally dependent or are mutually regulated by other sources. Under homeostatic conditions, both HSCs [6▪▪,23▪,25▪] and MSCs [25▪] have been consistently observed to localize peripherally near the bone surface rather than in the central medullary regions. The interface between vasculature and the endosteum represents a site of arteriolar sympathetic innervation [25▪] and circulatory exchange between arteriolar and venous vessels [23▪]. Therefore, the positioning of HSCs and MSCs at these bone-proximal perivascular areas may, in fact, poise them to receive instructive signals from neural [26] and endocrine [27▪▪] sources. The unique spatial configuration of these stem cell populations could be reflective of their mutual modulation by central regulatory control, allowing rapid responses to changing systemic conditions. In addition to the close physical associations shared between HSCs and MSCs [17], it is probable that the parallels between hematopoietic and mesenchymal organizational hierarchies may extend beyond the primitive compartment. MSCs are multipotent sources of both osteoblasts and adipocytes, mirroring dichotomous cell fate decisions made by HSCs as they commit to either lymphoid or myeloid development. Evidence has suggested that osteogenesis and lymphopoiesis appear to be occurring in tandem, as developing populations of B lymphoid progenitors are dependent on osteolineage cells in vitro[28] and in vivo[29▪▪,30▪▪,31,32]; however, osteogenesis can proceed in the absence of lymphoid cells [33]. Although bone marrow adipocytes have not been well examined outside the context of HSC regulation [16], functional coupling between adipogenesis and myelopoiesis is a possibility based on common molecular networks [34,35] and the biased bone marrow accumulation of both lineages with advancing age [36,37]. Collectively, emerging evidence suggests that the hematopoietic and mesenchymal hierarchies in the bone marrow may be to some extent functionally superimposed, with common elements contributing to their mutual regulation.

In addition to detailed characterization of the cellular complement in the immediate vicinity of phenotypic HSCs, multiple groups have also observed heterogeneous localization of functionally defined HSCs across the gross anatomical topography of bone marrow space [6▪▪,20,38,39]. Using rigorous xenotransplantation assays, we have recently performed phenotypic and functional analyses identifying that transplanted human HSCs nonrandomly localize with preference to the trabecular-rich metaphyses of murine long bones. Critically, this finding was reinforced by the examination of primitive hematopoietic populations according to trabeculation gradients within primary human trephine biopsies, confirming the direct clinical relevance of HSC spatial distribution within bone marrow [6▪▪]. Others have come to similar conclusions using congenic mouse systems, identifying enhanced reconstitutive capacities of HSCs based on their physical isolation from metaphyseal rather than diaphyseal regions [38,39]. Enriched homing and early reconstitution of HSCs has also been observed within metaphyseal bone areas under ablative [22▪▪,24] or nonablative [20] conditions. This selectively HSC-supportive potential has been collectively attributed to the unique molecular composition of trabecular osteoblasts [6▪▪], enriched bone remodeling activity in the long bone extremities [22▪▪], and the metaphyseal abundance of hyaluronic acid [20], a cognate ligand for HSC-expressed CD44 [40] (Fig. 1). Certainly, the physiological role of the hyaline growth plate is likely to substantially contribute to the nonuniform distribution of mesenchymal cell types within endochondral bones [41]. Ultimately, these studies provide strong evidence that spatial bone marrow localization can allow for the isolation of functionally superior HSC populations despite cell surface phenotypic equivalence [6▪▪,38,39], highlighting the instructive role of the microenvironment in defining and maintaining HSC cellular identities.

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MOLECULAR COMPOSITION OF THE HEMATOPOIETIC STEM CELL MICROENVIRONMENT

Despite the intuitive appeal of discretely defining the cellular constituents that reliably compose the HSC niche, the regulatory contribution of any supportive cell is likely to be dependent on its maturation status and functional state. The relevance of the cellular diversity within mesenchymal and endothelial lineages is becoming particularly appreciated in the context of HSC interactions. The originally perceived direct dependence of HSCs on the osteoblastic lineage is currently being reevaluated [42▪], based on reports that fluctuations in osteoblastic cell numbers can be achieved with negligible impacts upon the most primitive hematopoietic subsets [43,44] and suggestions that alternative cell lineages may be dominantly providing key HSC self-renewal signals [29▪▪,30▪▪,45]. Such variable observations could be in part attributed to the existence of osteoblast subpopulations that differ in their abilities to influence HSC behavior. We have demonstrated that spatial boundaries define molecularly distinct osteoblastic subsets, characterized by the enrichment of osteolineage cells expressing the Notch ligand Jagged-1 within highly trabeculated metaphyseal regions. This was reflected by a reciprocal activation of Notch signaling targets within highly repopulative trabecular HSC fractions, implicating a role for the Notch signaling pathway in maintaining functionally superior HSCs within specific anatomic areas [6▪▪]. Phenotypic heterogeneity has also been described within the vascular lineage, with expression of vascular endothelial growth factor receptor-3 distinguishing sinusoidal endothelial cells from arterioles [21]. This dissociation has been further suggested to inform the physical arrangement of HSCs in the bone marrow, which were reported to nonrandomly localize in periarteriolar rather than sinusoidal regions [25▪].

In addition to the considerable cellular heterogeneity within bone marrow-specific lineages, there also appears to be appreciable molecular overlap between HSC-trophic contributions across cell lineages. For example, in addition to the suggested significance of the osteoblastic expression of Jagged-1 [6▪▪,8], the detection and functional relevance of Jagged-1 has also been demonstrated in other bone marrow-resident populations including phenotypic MSCs [6▪▪] and vascular endothelial cells [46,47▪]. C-X-C motif ligand 12 (CXCL12) represents another HSC-supportive factor critical to early ontogenic survival [48] that also causes pronounced but nonfatal hematopoietic consequences if genetically removed in adulthood [49]. CXCL12 expression has been detected in multiple bone marrow cell types, the relevance of which has recently been examined by systematic conditional knockout studies [29▪▪,30▪▪]. Following lineage-specific CXCL12 ablation, the severity of hematopoietic phenotypes appeared to be in proportion with the overall magnitude of the bone marrow CXCL12 loss [30▪▪], with deletion from primitive Prx1+ mesenchymal populations leading to, particularly, dramatic HSC suppression [29▪▪,30▪▪]. Interestingly, HSCs and lineage-committed progenitors appear differentially sensitive to the dosage of bone marrow CXCL12, as osteoblast-specific deletion was sufficient to compromise developing lymphoid cells but not HSCs [29▪▪,30▪▪,50]. Using similar methodology, stem cell factor was equally identified as an important locally secreted factor predominantly provided by the endothelium and associated perivascular mesenchymal cells, with negligible contribution from osteoblasts [45]. Ultimately, it is unlikely that any single lineage would have the capacity to provide a sufficient complement or control of cellular signals to independently sustain HSC pools, and the spatial gradients and homeostatic significance of these molecules are only beginning to be defined [6▪▪,29▪▪,30▪▪,45].

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PHYSIOLOGICAL INFLUENCES ON HEMATOPOIETIC STEM CELL MICROENVIRONMENTS

Stem cell niches are generally conceptualized as fixed tissue spaces that serve to definitively instruct immature populations; however, niches themselves are dynamic and subject to turnover. For instance, niche-derived CXCL12 levels have been shown to consistently fluctuate according to circadian rhythms [51] and as a result of aged neutrophil disposal [52▪]. HSC fate decisions reflect these oscillations of the microenvironment, achieving a delicate balance between cellular elimination and production [51,52▪]. Systemic factors also contribute to microenvironmental regulation, with the potential to accelerate blood production under natural conditions of hematopoietic demand such as pregnancy [27▪▪]. However, extensive bone marrow remodeling is required to accommodate severe physiological demands for blood supply, such as recovery from myeloablative injury. During such departures from homeostasis, the activities of HSC self-renewal and differentiation are not only spatially segregated but are also organized following a strict temporal coordination of events.

Both megakaryocytes [13▪,53] and α-smooth muscle actin-expressing macrophages [54▪] have been identified as early-acting orchestrators of the regenerative cascade following radiation damage to the bone marrow. These cell types are both relatively radioresistant, allowing them to initiate repair processes through growth factor secretion [13▪,53,54▪] and structural reestablishment of bone marrow scaffolds [55▪]. Vascular integrity is also compromised by both chemotherapy and radiotherapy, requiring rapid reconstruction of the endothelial network. Evidence suggests that neoangiogenesis and hematopoietic restoration are obligately codependent processes, with endothelial vascular endothelial growth factor receptor-2 being critical for hematopoietic recovery despite its dispensability during homeostasis [21]. Cytoreductive insults have less visually overt effects on osteoblastic populations [21], although it has been reported that radioablation induces transient osteolineage expansion that is regionally restricted to metaphyseal trabeculae [53]. This osteoblastic response is fundamental to the recovery of primitive hematopoietic populations after radioablation [13▪], whose localization to trabecular surfaces becomes even more pronounced during regeneration than at homeostasis [22▪▪,24].

Early cellular bone marrow reconfiguration events collaborate to form a unique molecular milieu, encouraging acute self-renewing HSC expansions related to activated canonical morphogen pathways. Endothelial Jagged-1 provides critical recovery signals [47▪] and the balance of Wnt factors favors canonical signaling. This is achieved by microenvironmental attenuation of noncanonical ligands normally responsible for homeostatic HSC restraint [56]. The recovering bone marrow also experiences increased expression of HSC retention factors including CXCL12, which becomes particularly enriched in the metaphysis [53]. Macrophage-supplied prostaglandin E2 was similarly shown to be critical for HSC rescue following trauma [54▪], as it also prevents HSC release from the bone marrow [7▪]. Finally, HSC-stimulatory signals can, however, play counteractive roles if present during cytotoxic challenge. Although endothelial expression of E-selectin becomes amplified as part of the HSC-supportive injury response, high prechemotherapy levels present a survival disadvantage because this causes limited HSC quiescence [57▪▪]. Hematological complications of high-dose chemotherapy can, therefore, be minimized by prior inhibition of E-selectin [57▪▪], providing a potential new direct clinical application of bone marrow niche targeting.

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HEMATOPOIETIC STEM CELL LOCALIZATION IN PATHOLOGICAL CONDITIONS

It is not only necessary to develop an accurate understanding of HSC niche dynamics to more deliberately manage injury conditions but also important to understand how the HSC niche may be perturbed in pathological states. Many hematopoietic diseases are characterized by the loss or inappropriate regulation of the HSCs, and the etiologic participation of nonhematopoietic elements is now becoming recognized. For example, in a mouse model of Fanconi anemia, an MSC-proliferative defect has been suggested to underlie impaired HSC-supportive capacity, likely contributing to symptoms of bone marrow failure [58]. Cultured bone marrow stromal cells from a murine model of myelodysplasia offered poor support of normal HSCs, with little consequence for leukemic progenitors, indicating environmental restructuring specifically at the expense of healthy HSCs [59▪]. Xenograft experiments employing human cell lines have similarly suggested that HSCs become physically relocated to aberrant bone marrow niches in leukemic states, accounting for dysregulated hematopoietic functions [60]. A more recent study applied primary patient xenograft modeling to suggest that murine recipient HSC pools become transiently expanded during acute myeloid leukemia progression, despite their lack of hematopoietic output [61▪▪]. Not only can leukemia cells modify the bone marrow niche but mesenchymal cells can also be drivers of leukemogenesis; dysfunctional osteolineage cells can initiate karyotypic instability in primitive hematopoietic populations, ultimately leading to transplantable leukemic disease [62▪,63,64]. This not only reinforces the biological significance of osteoblast–HSC relations but also shows to be a phenomenon specific to osteoprogenitors rather than mature osteoblasts [63], substantiating the functional relevance of mesenchymal cell heterogeneity. Leukemic penetrance was also dependent on osteoblastic Jagged-1 expression [62▪], consistent with its role as a critical determinant of normal HSC self-renewal [6▪▪,8].

In addition to damaging consequences for HSC biology, leukemic reorganization of bone marrow appears to actively perpetuate disease progression. Rare, self-renewing leukemic stem cells (LSCs) have, however, been reported to be surprisingly niche dependent [65], potentially representing a unique and targetable vulnerability. A thorough understanding of the LSC niche will therefore be required to evaluate the potential therapeutic value of targeting leukemic disease through the bone marrow microenvironment [66▪]. It has been proposed that similar to the normal hematopoietic system [7▪,45], distinct niches are occupied by different primitive cellular subsets of the same disease [67]. Others have suggested that LSC niche preference may also be disease specific. In a comparative assessment of murine LSCs from acute or chronic models of myeloid leukemia, chronic myeloid leukemia (CML)–LSCs were suppressed but AML–LSCs were exacerbated following osteoblastic parathyroid hormone receptor activation [68▪▪], which has been previously linked to HSC expansion [8]. This observation reconciles previous reports that suggested divergent influences of leukemia on osteoblastic populations in mouse models of myelodysplasia [59▪] versus a more acute myeloid disease [69]. The contrasting properties between AML–LSCs and CML–LSCs may indicate that they represent caricatures of different levels of the hematopoietic hierarchy, respectively [70,71], as HSCs and hematopoietic progenitor cells are likewise subject to dissociable extrinsic regulation [7▪,29▪▪]. In fact, descriptive observations have accordingly suggested that human AML–LSCs preferentially localize to HSC-characteristic endosteal regions [72,73], although limited evidence has outlined whether they are functionally restricted to the same ecological range in the bone marrow. It will become increasingly important to detail the physical and molecular overlap between HSCs and AML–LSCs in the bone marrow cavity in order to appropriately inform the development of novel selective therapeutic strategies. Because CML–LSCs are arguably less likely to directly cohabitate with normal HSCs, pharmacological targeting of the bone marrow microenvironment may provide a tangible therapeutic option in this context. However, more innovative therapeutic approaches may be required to better eliminate AML–LSCs without compromising HSC pools that are potentially regulated in a similar fashion.

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CONCLUSION

Although traditional reductionist approaches have provided foundational underpinnings for HSC niche biology, further conceptual advancement will require an integrated appreciation for the composite of inputs regulating HSC behavior. Beyond cell surface markers, HSC phenotypes are defined by both spatial and temporal conditions that dictate their functional performance according to demand. These insights have immediate clinical relevance, with the potential to inform the procurement of functionally superior HSCs for transplantation [6▪▪], HSC preservation during ablative therapy [57▪▪], or direct therapeutic targeting of unique LSC niches [68▪▪]. Ultimately, complementary studies incorporating human investigation in parallel with functional preclinical mouse models [6▪▪,7▪] will be of critical significance to rapidly derive translational value and accelerate clinical application.

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Acknowledgements

The authors would like to thank Claudia Hopkins for generating the illustration for this article. They would also like to thank Dr Borhane Guezguez, Dr Mio Nakanishi, Dr Tony Collins, and Lili Ostovar for their valuable suggestions and comments. The authors’ research described was funded by the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society Research Institute (CCSRI). M.B. is supported by the Canadian Chair Program and holds the Canada Research Chair in human stem cell biology. A.L.B. has been supported by graduate scholarships from the Natural Sciences and Engineering Research Council of Canada, the Ontario Graduate Scholarship Program, and the Jans Graduate Scholarship in Stem Cell Research.

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Conflicts of interest

There are no conflicts of interest.

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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

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Keywords

bone marrow microenvironment; hematopoietic stem cell; heterogeneity; niche; self-renewal

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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