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. Author manuscript; available in PMC: 2022 Jul 1.
Published in final edited form as: Curr Opin Hematol. 2021 Jul 1;28(4):243–250. doi: 10.1097/MOH.0000000000000656

Cellular components of the hematopoietic niche and their regulation of hematopoietic stem cell function

Joydeep Ghosh 1, Roy El Koussa 2, Safa F Mohamad 3, Jianyun Liu 1, Melissa A Kacena 4,5, Edward F Srour 1,2,6
PMCID: PMC8169581  NIHMSID: NIHMS1693241  PMID: 33966008

Abstract

Purpose of Review:

Development and functions of hematopoietic stem cells (HSC) are regulated by multiple cellular components of the hematopoietic niche. Here we review the recent advances in studying the role of three such components - osteoblasts, osteomacs and megakaryocytes and how they interact with each other in the hematopoietic niche to regulate HSC.

Recent findings:

Recent advances in transgenic mice models, scRNA-seq, transcriptome profile, proteomics and live animal imaging have revealed the location of HSC within the bone and signaling molecules required for the maintenance of the niche. Interaction between megakaryocytes, osteoblasts and osteomacs enhances hematopoietic stem and progenitor cells (HSPC) function. Studies also revealed the niche as a dynamic entity that undergoes cellular and molecular changes in response to stress. Aging, which results in reduced HSC function, is associated with a decrease in endosteal niches and osteomacs as well as reduced HSC-megakaryocyte interactions.

Summary:

Novel approaches to study the cellular components of the niche and their interactions to regulate HSC development and functions provided key insights about molecules involved in the maintenance of the hematopoietic system. Furthermore, these studies began to build a more comprehensive model of cellular interactions and dynamics in the hematopoietic niche.

Keywords: Osteoblasts, osteomacs, megakaryocytes, hematopoietic stem cells, hematopoietic niche

INTRODUCTION

The concept of the hematopoietic niche (HN) was first introduced by Schofield in 1978. By then however, Dexter had already showed experimentally that bone marrow (BM)-derived stromal cells isolated from the hematopoietic microenvironment can maintain granulopoiesis (1). In his landmark publication (2), Schofield proposed that hematopoietic stem cells (HSC) associate with other cells in the niche thus allowing these cells to determine HSC behavior. After many years of intense investigations, we now know with more certainty, that the behavior of HSC is definitely determined by other cell types as well as extracellular proteins present in the HN (3–11). Over the last 40 years, researchers have illustrated that the niche is a complex structure of multiple cell types that interact together and with HSC to maintain stem cell self-renewal potential and to preserve the competence of the niche (6, 12–14). Among the early studies further characterizing cellular components of the niche were those of Taichman et al (15). These were followed by investigations from Zhang et al. (16) and Calvi et al. (17) who illustrated that bone-lining osteoblasts (OB) associate with HSC and are critical elements of the niche. A very recent study that examined four mice genotypes, confirmed that the HN is characterized by an abundance of microenvironmental cell types, thus expanding the “players” within the niche to include many cellular types that normally reside within the hematopoietic microenvironment (**18). HSC maintenance is associated with the health of cellular elements of the niche including endothelial and perivascular cells, OB, neuronal and glial cells, and other hematopoietic cells including megakaryocytes (MK) (19–21), macrophages (22–25), and osteomacs (OM) (26–28). The cooperative and supportive interactions among several niche cellular elements to generate an augmented degree of HSC support has not been examined rigorously. It is only logical to assume that members of a sophisticated and intricate microenvironment partially responsible for the homeostatic control of the hematopoietic system and maintenance of its matriarchical epitome, the HSC, would cooperate synergistically and/or additively to sustain such a responsibility. Evidence for such a cooperation is evident in many investigations examining how cytokines and growth factors influence and maintain cellular elements of the niche (9, 10, 29), how macrophages orchestrate hematopoietic programs in the niche during inflammatory stress (25), or the proximity of HSC to other cell types in the niche including MK (**18). The issue of proximity of HSC to nurturing cells in the niche has been previously exploited to identify molecules and signals that promote stem cell survival and regulation (30). Advances in technologies have increased our understanding of the HSC and its niche to a great extent. Mass spectrometry technique like CyTOF, which tags antibodies with heavy metal ions, had been utilized to determine expression of 32 proteins simultaneously on bone stromal cells (**31). Here, we review the recent advances in understanding the roles OB, MK and OM play to regulate HSC function and how these cellular components of the niche interact with each other to regulate hematopoiesis.

ROLE OF OSTEOBLASTS IN THE HEMATOPOIETIC NICHE

OB are located at endosteum of the bone and considered as the anchor cell population of the endosteal niche (**32). In the 1970s, OB were the first component of the niche to be associated with hematopoiesis. Colony forming assays (CFU) along with thymidine suicide techniques showed that HSPC were enriched closer to the endosteal niche (33, 34). Later studies showed that OB have a hematopoiesis enhancing activity (HEA) in vitro (15, 35–37). In addition, after bone marrow transplant (BMT), murine HSC preferentially home to the endosteal region of the bone (38, 39). Ablation of OB resulted in reduced numbers of HSC in the bone along with an concomitant increase in extramedullary hematopoiesis (40). In contrast, an increase in OB number resulted in an increase in HSC numbers (16, 17). Interestingly, in aged mice, conditional deletions of Ebf1 and Ebf3 in CXCL12-abundant reticular (CAR) cells result in increased OB along with reduced HSC numbers in bone and subsequent extramedullary hematopoiesis (41). These examples demonstrate that while OB number is critical, it is not the sole determinant to maintain HSC function. OB also play an important role in regulating HSC stress response. Although 5-Fluorouracil (5-FU) administration results in death of mature OB along with a global reduction in expression of osteogenic genes in stromal cells, it also upregulates the frequency of a small subset of osteolineage cells (Col16a1high Tnnhigh) expressing increased Wnt5a (*42). Ryk, a Wnt ligand receptor, interacts with Wnt5a to maintain HSC quiescence and confer protection to HSC following myeloablative stress (43, 44). It is possible that increased Wnt5a expression in osteolineage cells reduce proliferation rate of a subset of HSC to protect them from DNA damage and apoptosis after chemotherapy. Interestingly 5-FU did not affect the endosteal niche in old mice (*45), suggesting a change in stress response with age. Moreover, after irradiation, OB in the endosteal region change from a single layer to multi-layer and become cuboidal, possibly to aid HSC recovery (46).

The precise mechanism(s) detailing how OB regulate HSC maintenance and function are still unclear. Using CyTOF on bone stromal cells, Severe et al. recently demonstrated that a subset of osteolineage cells express key hematopoiesis regulatory cytokines including SCF and SDF1 (**31). However, conditional deletion of Scf and Cxcl12 in OB progenitors or in mature OB did not alter hematopoiesis (29, 47, 48). As other cell types in the HN also express key cytokines including SCF, SDF1, GM-CSF, and TNF-α at a similar level as OB (**31), It is therefore possible that instead of OB, other cells are the major paracrine regulators of HSC. Studies have also identified multiple proteins including transcription factors and adhesion molecules in OB-mediated maintenance of HSPC. Impaired Wnt signaling in OB of Wlsfl/fl-Col2.3Cre mice results in reduced bone volume. However, only in aged Wlsfl/fl-Col2.3Cre mice, HSC became more senescent along with decreased functional potential and increased radio susceptibility (49). A recent scRNA-seq study of bone marrow stromal cells had identified two distinct osteolineage cell subsets: OLC-1 and OLC-2. OLC-1 cells, which includes early osteoprogenitors, express higher level of Runx2 compared to OLC-2 subset (*50). Previous studies have also shown that immature osteolineage cells express increased level of Runx2, and the expression level of Runx2 corresponds to the HEA of these cells (36). This suggests that immature osteolineage cells are potent in expanding HSPC in vitro compared to mature OB. CD166, another protein expressed on immature OB, is also critical for maintenance of HSPC in vitro and homophilic engagement of CD166 expressed on OB and HSPC is required for HEA (51, 52).

Recent studies have also raised questions whether HSC reside predominantly near the endosteal niche. In a mouse model (α-catulinGFP/+), deep tissue imaging revealed that more than 80% of HSC reside more than 90 μm away from trabecular and cortical bone as well as bone matrix (**18). The study found only a minor fraction of HSC resides near trabecular and cortical bone surfaces. However, in steady-state, HSC might be more dynamic to be localized within a specific area. Recent study of live imaging of long bones and calvarium of Pdzk1ip1-CreEr R26LSL-Tom mice showed that the bulk of the HSC are motile within the niche and have a long-range motion spectrum (**53). Contrarily, in Mds1GFP/+ Flt3 Cre mice, time-lapse imaging revealed that very few HSC in calvaria are motile in nature at steady-state (**54). Interestingly, the study also found that quiescent HSC reside within 10 μm of both sinusoidal blood vessels and endosteum, whereas HSPC locations are far more diverse (**54). These differences could be attributed to any potential difference in HSC subset labelled in either study. Contrarily, in the context of BM transplant, human HSC have shown less motility and they lodge in the endosteum, suggesting a role for OB in regulating HSC localization (55). One possible reason for this discrepancy could be the difference between steady-state and stressed niches. Furthermore, OB could be the preferred niche for varying types of HSC that have distinct functional properties. Based on CD49b expression, HSC can be further subdivided into reserve HSC (rHSC; CD49b- SLAM-LSK), and primed HSC (pHSC, CD49b+ SLAM-LSK) (*56). rHSCs are more quiescent compared to pHSCs, reside on top of the stem cell hierarchy and localize closer to the endosteal surface. Following chemotherapeutic stress, the majority of the surviving rHSC are located near the endosteal region. N-cadherin expressing stromal cells, which have an osteogenic potential and express high levels of osteogenic genes, are responsible for protecting rHSCs (*56).

What adds to the complexity of niches in terms of their ability to regulate HSC function is that HN dominated by osteolineage cells are not uniform. Studies have shown that the bone microenvironment is dynamic in nature. Three different types of cavities have been identified within bone based on bone turnover: i) predominantly OB (D-type), ii) predominantly osteoclasts (R-type), and iii) mixed (M-type). In steady state, similar number of HSC reside in all 3 cavities. Following activation by G-CSF, proliferating HSC cluster within M cavities (**54). Combined with the motility and heterogeneity of HSC, remodeling of the bone and effect of external stimuli, it can be hypothesized that the interaction between HSC and niche is a dynamic process.

ROLE OF MEGAKARYOCYTES IN THE HEMATOPOIETIC NICHE

MK have been identified as a component of the hematopoietic niche. 3D quantitative imaging has revealed that HSC associate closely with MK (57). Recent studies have demonstrated that a subset of HSC in young adult mice reside within 5–10μm of MK (**18, *45, *56) and the distance increases with age (45). Under physiologic conditions, the MK promote HSC quiescence through the secretion of CXCL4 and TGFβ1. Animal models where Cxcl4 or TGFβ1 were knocked out, or MK were depleted, showed decreased quiescence and increased HSC pool size (57, 58), signs of lack or decreased HSC function. A more recent study has shown that distinct hematopoietic niches exist in the marrow (12). Direct effects of MK on HSC activity were observed specifically on myeloid-biased HSC characterized by von Willebrand factor (vWF) expression that were found in association with MK-enriched niches (59). Another study using imaging and computational simulations, stipulated that MKs, due to their sheer size, may act as a physical barrier to the migration of HSC out of the marrow cavity and into peripheral circulation, further modulating HSC pool size (**60). In addition to CXCL4 and TGFβ1 secretion, MK have also been shown to be a main producer of thrombopoietin (TPO) (61). Extensive research has implicated TPO and its receptor, c-MPL, in the modulation of hematopoietic activity (62, 63). MK-depleted mice showed decreased megakaryopoiesis as well as lower numbers and reduced quiescence of HSC. Upon treatment with recombinant thrombopoietin, the number of quiescent HSC in the same animal model was restored to normal values (61). However, it was recently shown that the hepatic production of TPO is chiefly responsible for these effects on HSC. Animal models where the Tpo was selectively knocked out from hematopoietic and stromal cells showed normal marrow composition and HSC reconstitution potential (64).

On the other hand, if MK maintain HSC quiescence, then how can the increase in HSC pool size, observed with aging, be explained, despite a concordant increase in MK numbers? Multiple studies have explored the myriad of changes observed in HSC during aging (**65), including, but not limited to, reduced regenerative potential (66), myeloid skewing (67, **68), accumulation of reactive oxygen species (ROS) and subsequent DNA damage (69, 70), and metabolic alterations (71). Any of these changes could have a major impact on HSC pool size. However, when it comes to the niche, and more specifically MK, two recent studies (*45, **68) found that with aging, despite the expansion of HSC and MK, the two cell types locate farther away from each other in the niche, which might explain the effects of MK on HSC and the age-related observed reduced HSC quiescence. Interestingly, Ho et al also showed that during aging, there is a reduction in endosteal niches (compared to MK-enriched, sinusoidal niches) (**68). This latter finding might be attributed to the reduced capacity of MK to stimulate OB expansion with aging, leading to bone loss (*72). The increased distance between HSC and MK as well as the reduced capabilities of MK to stimulate OB expansion could explain the decreased HSC quiescence observed in aged animals in the studies of Ho et al (**68).

ROLE OF OSTEOMACS IN THE HEMATOPOIETIC NICHE

Macrophages are important immune cells phagocytosing cellular debris, microbes, and cancer cells, as well as playing essential roles in maintaining tissue homeostasis (73). OM are bone-resident macrophages and part of the endosteal and periosteal bone lining tissues (23). OM form a canopy-like structure over the endosteal surface, associating with bone-forming OB and facilitating bone remodeling (23, 27, 74, 75). OM share many similar phenotypical markers of bone marrow-derived macrophages (BMM): they both express, at different levels, CD45, F4/80, CD68, CD11b, Mac2, Ly-6G and CD169 (27). Tissue-resident macrophages originate from two possible sources: circulating monocytes (via HSC differentiation) or proliferation from embryonically-derived macrophages (76). So far little is known whether OM are from monocytes (thus of hematopoietic origin) or embryonic macrophages. Studies suggest that OM are derived from HSPC (77) (Mohamad et al, unpublished data, a) and are therefore possibly share a close origin with the BMM.

Although the role of OM in bone regeneration has been established (23, 78), little is known whether OM are important in hematopoiesis. Suppressing macrophages in the bone marrow by genetic (MaFIA mice, LysMCre-DTA, CD169Cre-DTR and CD11bCre-DTR) and pharmacological approaches (G-CSF and clodronate liposomes) results in increased HSC in the circulation, indicating that macrophages in the BM are important components of the HN and contribute to HSC maintenance, niche retention and function (24, 78–80). However, these works could not unequivocally prove that only macrophages are responsible for these functions since OM share these phenotypic markers (27) and are capable of phagocytosing (Mohamad et al, unpublished data, b). Based on our studies, we hypothesize that OM have distinct functional properties from BMM (27). Furthermore, our work showed that a very small subset of OM have a unique co-expression of CD166 and CSF-1R (27) which is not shared by BMM. Similar to OB (51), CD166 expression on OM is also required for enhancing hematopoiesis activity, probably via the homophilic interaction of CD166-CD166 or possible interaction between CD166 and Embigin (81) (Mohamad et al, unpublished data, a). Given that both CSF-1 deficient and CSF-1R KO mice demonstrate reduced bone absorption (82), expression of CSF-1R on OM is consistent with their crucial function in osteopetrosis as previously shown by us and others (23, 27, 75) and suggests that OM are mature and differentiated cells (83).

OM have a special shape, function and spatial position in the bone, which make them unique candidates in bringing together other cell types in the HN. We have previously demonstrated that neonatal calvarial cells (NCC, mostly OB and contain between 3–4% OM) enhance HSC function and are important to the hematopoietic niche (35, 51). Neither OB nor OM by themselves can enhance HSC function to the same level as when both cell types are combined together (Mohamad et al, unpublished data, a). Additionally, MK are shown to work together with calvarial cells and enhance HSC function (21, 27) (Mohamad et al, unpublished data, a). Our recent work suggests that MK enhance OM proliferation and thus promote HSC function when cocultured with NCC and HSC (27). Of note here is that BMM could not replace OM functionally thus raising the question of whether all or most of the hematopoietic functions previously attributed to marrow-derived macrophages, are indeed those of OM. Compared to BMM, OM have increased potential to differentiate into TRAP+ osteoclast, an important component of the niche. Moreover, they maintain HSC pool and impact homing (27, 84). Additionally, OM derived from either neonatal or adult mice can enhance hematopoietic function (27). Therefore, OM, although low in numbers, are likely to be important in bridging OB, MK and HSC together in the hematopoietic niche.

THE INTERACTIONS BETWEEN HSC, OB, MK AND OM

The interplay between OM, MK, OB and HSC seen in homeostasis, aging and stress response suggests that the regulation of hematopoietic activity by the cellular components of HN is not limited to the direct effects on HSC. MK inhibit OB differentiation, partly through modulation of Pyk2 phosphorylation, a negative regulator of OB differentiation (85). More recently, Lee et al. showed that conditioned media from MK is able to promote expansion of OB while suppressing differentiation (86). We have previously shown that immature OB have a higher hematopoietic enhancing activity when compared to mature OB (35, 36). These suggest that in homeostatic conditions, MK inhibit OB differentiation to maintain its HEA. It is important to note that the effect of MK on OB differentiation remains controversial, with a group showing that MK promote OB differentiation through secretion of TGFβ (87). Interestingly, MK need to maintain physical contact with OM, but not HSPC to enhance engraftment (Mohamad et al, unpublished data, a) suggesting MK regulate HN both by secretory proteins as well through physical contact.

MK have been shown to play an important role in niche remodeling after radioablative treatment, primarily through their effect on osteolineage cells (88). After total body irradiation, MK migrate to the endosteal niche via TPO signaling where they promote OB expansion and niche remodeling via the secretion of PDGF-β. This remodeling of the hematopoietic niche is required for a more successful engraftment of HSC following total body irradiation (88). As a section of OM can also survive irradiation (Mohamad et al, unpublished data, a), it is possible that interactions between OM and MK play a role in HSC engraftment in irradiated recipients. In aged mice, although MK numbers are increased they have reduced potential to stimulate OB expansion (*72). Given old mice also have reduced OM and OB number (89) (Mohamad et al, unpublished data, a) along with a decrease in HSC engraftment and myeloid bias (90, 91), it is likely that aged MK lose their HEA potential despite an increase in number (Fig. 1). Moreover, aging also causes remodeling of the niche (**68, 92, 93). Aged mice display reduced osteoprogenitor cells along with an overall decline in the endosteal niche area (**68, 93), which is also functionally disadvantaged compared to young niche (*45). When HSC isolated from young mice were transplanted into either young or old mice, they localized further from endosteum (>50μm) and closer to the sinusoidal niche in old mice (*45). However, in young recipients, these transplanted HSC were evenly distributed within the niche, with a subset of HSC localized within 0–50μm of the endosteum (*45). This change in niche behavior demonstrate that localization of HSC could alter with the functional competence of the niche. Overall, recent studies have revealed that the niche is a dynamic cellular entity that changes differently with age, and stimuli like G-CSF treatment, 5-FU treatment and irradiation.

Figure 1.

Figure 1.

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Schematic of the hematopoietic niche throughout age. In young mice, HSC, OB, OM and MK are located close to each other within the same neighborhood. In aged mice HSC move away from Mk towards perivascular niche and show reduced regenerative potential. Also, with aging, HSC and MK numbers increase whereas OM numbers decrease and mesenchymal stromal cells undergo a shift from osteogenic differentiation to adipogenic differentiation.

CONCLUSION

Since Schofield’s proposal of hematopoietic niche, our understanding of it has developed considerably with the advances in HSC-specific reporter mice, scRNA-seq, cyTOF, full bone section as well as live animal imaging. In future, with these novel tools widely available, we should have a more comprehensive picture of how the cellular components regulate hematopoiesis and how they can be targeted for therapeutic approaches.

KEY POINTS.

  • The understanding of localization of HSC and niche cells that regulate HSC development and function has evolved over time.

  • The localization of HSC within the hematopoietic niche is dynamic and changes with age, stress and irradiation.

  • Crosstalk between MK, OB and OM promote HSC function.

  • Better understanding of the cellular crosstalk at the molecular level of hematopoietic niche might be key to improving HSC function.

Financial support and sponsorship:

This work was supported by NIDDK grant R01 DK118782 (EFS) and was also partially supported by NIAMS grant R01 AR060332 (MAK).

List of Abbreviations

HSC

Hematopoietic stem cells

HSPC

Hematopoietic stem and progenitor cells

HN

Hematopoietic niche

BM

Bone marrow

OB

Osteoblasts

OM

Osteomacs

MK

Megakaryocyte

CFU

Colony forming unit

HEA

Hematopoiesis enhancing activity

BMT

Bone marrow transplant

CAR

CXCL12 abundant reticular

5-FU

5-fluorouracil

vWF

von Willebrand factor

TPO

Thrombopoietin

BMM

Bone marrow-derived macrophages

NCC

Neonatal calvarial cells

Footnotes

Conflicts of interest: None

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