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BM niche dysregulation in MPN
as osteoclasts originate from CD34+ hematopoietic cells.23 Early work showed that the two populations were func- tionally interdependent, e.g. osteoblasts constitutively expressed G-CSF and CD34+ hematopoietic cells enhanced IL-6 production by osteoblasts hence stimulat- ing further investigations into these interactions.24,25 It is accepted that, in general, osteoblast functionality plays an important role in HSC maintenance, in particular with regard to HSC trafficking. Regulatory roles depend upon osteoblastic differentiation stage, whereby the immature osteoblast progenitor population influences HSC mainte- nance/proliferation and the mature osteoblasts modulate their differentiation.26 In murine models, Calvi et al. demonstrated that osteoblastic cells influenced HSC func- tional capacity through NOTCH activation, and it was suggested that HSC are located in close physical proximity to SNO cells, although the role of N-cadherin in these ‘cell-cell’ interactions remains under debate.27,28 Multiple soluble factors derived from the osteoblast population play a role in HSC pool fate, including CXCL12, angiopoi- etin-1 and osteopontin, in addition to multiple other cytokines/chemokines.29 CXCL12 is a CXC chemokine produced by stromal cells, the major source is from BMSC but also by osteoblasts influenced by circadian oscillations and there is evidence that CXCL12/CXCR4 signaling plays a pivotal role in modulation of HSC trafficking.30 In addition, the acidic matrix glycoprotein osteopontin is produced by pre-osteoblasts and osteoblasts and negative- ly regulates both HSC pool ‘size’ and egress.27,31 Of note, osteoblasts play an additional role in T lymphopoiesis, whereby DLL4 on the cell surface is pivotal for the pro- duction of ‘thymic seeding’ T progenitors.32
As introduced above, osteoclasts derived from mono- cyte-macrophage lineage cells in the presence of receptor activator of nuclear factor-κB-ligand and macrophage colony-stimulating factor play multiple regulatory roles within the niche in addition to their bone resorption char- acteristics.33 Kollet et al. demonstrated that, through endosteal component degradation, osteoclasts can pro- mote HSC mobilization.34 However, the literature also includes contrasting evidence concerning their exact role within the HSC niche, which is most likely context dependent. For example, using the osteopetrotic ‘OC/OC’-murine model, absence of functional osteoclasts induced a defective HSC niche with increased mesenchy- mal precursors, impaired osteoblast development, and resultant aberrant HSC homing.35 However, Miyamoto et al. evaluated hematopoietic activity in three murine mod- els without osteoclasts and showed that HSC mobiliza- tion was, in fact, similar, or indeed higher, than that of wild-type animals, suggesting that osteoclasts are not essential for HSC mobilization.36 Lastly, there is a great deal of cross-talk and interdependency between the osteoblast and osteoclast populations. It has also been shown that osteoclasts can act as antigen presenting cells and activate both CD4+ and CD8+ T cells.37
The vascular niche is the other pivotal component of the bone marrow niche and broadly encompasses thin-walled sinusoidal blood vessels, arterioles, transition zone ves- sels, endothelial cells (that also produce CXCL12), stromal elements, fibronectin, and collagen. Functionally, interac- tions between these perivascular elements determine both HSC dormancy/expansion and migration properties. By way of example, Akt activation in endothelial cells follow- ing mTOR recruitment induces upregulation of specific
angiocrine factors which promotes expansion of cells with LT-HSC repopulation capacity.38 Cell-cell contact also appears key. For example, E-selectin expression by endothelial cells in the vascular niche can regulate HSC dormancy and HSC proliferation.39 Moreover, the vascular niche provides an environment rich in multiple pro- inflammatory chemokines/cytokines, which contribute to niche maintenance. The so-called ‘hypoxic-gradient’ plays a major role in spatial HSC location within the vascular niche. In this way, quiescent HSC preferentially locate to small arterioles, unsheathed by rare NG2-pericytes, pre- dominantly found in the endosteal bone region. HSC tend to exhibit a strong hypoxic profile, promoting quiescence, irrespective of localization.40,41 Likewise, in those situa- tions whereby the sinusoids are under stress induced by, for example, myeloablative chemotherapy or irradiation, the endosteal niche becomes an important host of HSC and promotes quiescence.42
Bone marrow mesenchymal stem cells encompass a diverse group of cells with multipotent differentiation and self-renewal properties indispensable for HSC mainte- nance. BMSC can interact in a pleotropic fashion with HSC including direct cell-cell interaction and by the altered production of cytokines and cell markers.43 CXCL12-abundant reticular cells are a subpopulation of BMSC that produce CXCL12 and regulate the mainte- nance and quiescence of the HSC pool. Multiple other cell types, outside the remit of this review, contribute to the regulation of the niche including macrophages which modulate the CXCL12 pathway promoting HSC reten- tion, and monocytic-lineage cells which regulate osteoblasts, facilitate HSC mobilization and also encour- age a pro-inflammatory cytokine environment.31 Concerning the role of the sympathetic nervous system, Mendez-Ferrer et al. demonstrated that circulating HSC and their progenitors exhibit marked circadian fluctua- tions regulated by noradrenaline secretion by the sympa- thetic nervous system.30,44 Adrenergic signals via the beta- (3)-adrenergic receptor mediate downregulation of CXCL12 and there is a close association between so-called Nestin+ BMSC and adrenergic nerve fibers of the SNS with resultant regulation of HSC functionality and egress. This neuro-hematopoietic axis is exploitable as a therapeutic target, as will be discussed later.
With regard to the extracellular matrix (ECM), this is a non-cellular space that supports the integrity, proliferation and ‘elasticity’ of the entire bone marrow niche. It acts as a pivotal HSC ‘regulator’ and ECM-related components critically determine the functionality of HSC lodged with- in its confines.45 The ‘core matrisome’ is a complex struc- ture that consists of up to 300 protein components, enzymes, and growth factors (e.g. TGFβ1, PDGF and VEGF), and overall functionally drives maintenance of the HSC pool.
Bone marrow niche / extracellular matrix disruption in myeloproliferative neoplams
Myeloproliferative neoplasm-associated bone marrow niche homeostasis is disrupted on many levels which col- lectively can promote the proliferation, survival and migration of mutated MPN HSC. As described by Mead and Mullaly, both ‘host’ and extrinsic factors can influence MPN HSC behavior, and as the malignant clone expands,
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