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Y-H. Ho and S. Méndez-Ferrer et al.
Nestin-GFPdim and LepR+ cells are located.31 Recent studies also reveal that megakaryocytes, which are mostly adja- cent to sinusoids, regulate HSC quiescence through trans- forming growth factor-β, thrombopoietin and platelet fac- tor-4 secretion.32-34 Currently, it remains controversial which specialized niches predominantly regulate HSC quiescence. It is possible that HSC quiescence is different- ly regulated between steady-state and emergency and/or malignant hematopoiesis. However, lineage commitment appears to be influenced by the location of HSC and their derivatives in the BM. Accumulating evidence suggests that lymphopoiesis preferentially occurs near the endos- teum, while myelopoiesis/erythropoiesis/megakary- opoiesis mostly takes place in non-endosteal BM regions. Supporting this concept, a recent study using Vwf-eGFP to label different HSC populations demonstrated that Vwf+ platelet/myeloid-biased HSC are associated with megakaryocytes, whereas Vwf- lymphoid/unbiased HSC are located close to arterioles.35 Therefore, alterations in specialized niches might directly affect myeloid/lymphoid output, and the imbalanced production of mature hematopoietic cells at specific niches might in turn remod- el the local microenvironment for these cells.
Hematopoietic stem cells change location as niches are remodeled during aging
A growing body of evidence has indicated that HSC redistribute within the BM upon aging. For instance, aged HSC locate away from the bone surface (endosteum), compared with young HSC, upon BM transplantation.36 This abnormal homing behavior correlates with increased BM HSC numbers and enhanced HSC egress into the cir- culation.37 Recent studies using whole-mount immunoflu- orescence staining of murine long bones further revealed that aged HSC are more distant from the endosteum, arte- rioles, Nestin-GFPhigh cells and megakaryocytes, but HSC distance from sinusoids and Nestin-GFPlow cells appears unchanged, compared with that of young HSC.38-40 These results strongly suggest that the BM microenvironment is altered with age, favoring HSC lodging near non- endosteal (central) niches, over endosteal niches. The fol- lowing sections will discuss current studies on age-related BM niche remodeling, the key microenvironmental play- ers and the associated mechanisms by which HSC local- ization and function are regulated.
Dysfunction of bone marrow mesenchymal stromal cells
Studies regarding the absolute number of BM mes- enchymal stromal cells (MSC) during aging have yielded controversial results, with some suggesting an overall increase,41,42 while others suggest unchanged43,44 or reduced numbers.45 It is noteworthy that BM MSC are heteroge- neous, and the heterogeneity in the markers used to define BM MSC immunophenotypically might explain some of these controversies. Using Nestin-gfp to label murine BM MSC, different studies have reported reduced endosteal Nestin-GFP+ cells in the aged BM,39,40 consistent with reduced numbers of arteriolar αSMA+, PDGFRβ+ and NG2+ cells.38 The age-related contraction of endosteal BM might initiate lymphoid deficiency, since lymphoid niches have been previously described near bone.29,46-48 However,
this notion has been refined more recently after elucidat- ing dynamic interactions between B-cell progenitors and perivascular BM MSC, which provide key signals for B lymphopoiesis (such as Cxcl12 and Il7), both in endosteal and central sinusoidal BM niches.49-52 Functionally, old BM MSC exhibit reduced colony-forming unit-fibroblast (CFU-F) capacity in vitro and reduced expression of HSC niche factors.38 In this regard, revitalizing BM MSC to restore HSC niche factors has been proposed as a strategy to prevent DNA damage in cultured HSC.53
BM MSC exhibit reduced osteogenesis with age, which is associated with lower osteopontin secretion to the extracellular matrix.54 Osteopontin negatively regulates HSC proliferation,55-57 and its decline might accelerate HSC divisions during aging. Supporting this idea, treatment with thrombin-cleaved osteopontin partially reverses the age-associated phenotype of HSC.54
CC-chemokine ligand 5 (CCL5), a pro-inflammatory cytokine involved in bone remodeling,58 is reportedly increased with age. Researchers also reported a direct contribution to myeloid-biased differentiation at the cost of T cells by CCL5,19 suggesting that CCL5 is important for aging of the hematopoietic system and the microenvi- ronment. In contrast, old BM MSC show adipocyte skew- ing.59 Adipocytes are a BM niche component that pro- motes HSC regeneration after irradiation, although their roles in hematopoiesis under homeostasis seem to be dis- pensable.60 However, altered functions of adipose tissue, including ectopic lipid deposition, insulin resistance and increased inflammation, have been described during aging.61 Accumulation of BM adipocytes upon aging not only reduces hematopoietic reconstitution, but also dis- rupts bone fracture repair.62 The latter likely contributes to the increased risk of osteoporosis and bone fracture in the elderly population.63,64
BM aging is also associated with senescence of BM MSC, evidenced by increased p53/p21-mediated DNA damage, upregulation of p16(INK4a) and elevated levels of reactive oxygen species.65-67 An age-dependent shortening of telomeres was found in telomerase-deficient (Terc-/-) BM MSC; consequently, lethally-irradiated Terc-/- mice carrying wildtype BM cells display accelerated myelopoiesis.68 More recently, proteome analyses of human BM have unraveled nitric oxide synthesis and the urea cycle path- ways as potential mediators for the crosstalk between old BM MSC and HSC.69 Murine BM MSC show compara- tively higher mRNA expression of neuronal nitric oxide synthase (encoded by the Nos1 gene), as compared with other nitric oxygen synthase isoforms, and Nos1-/- mice develop certain features of premature aging, such as remodeled BM vasculature and myeloid skewing.39 Given the importance of nitric oxide in vascular biology and bal- anced inflammatory responses, it is likely that nitric oxide pathways participate in the aged vascular remodeling and myeloid expansion partly by modulating inflammation.
Remodeling of bone marrow vasculature and endothelial cell functions
During aging, remodeling of the BM endothelial vascu- lature is notable. Studies using whole-mount confocal imaging, two-photon intravital microscopy and flow cytometry analysis demonstrated overall increased vascu- lar density in aged mice.38,70 Yet distinct vascular beds show different, or even opposite alterations with age. Arterioles appear to be decreased, while sinusoids seem
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haematologica | 2020; 105(1)