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Niche alterations promoting hematopoietic aging
Table 1. Microenvironmental players contributing to hematopoietic stem cell aging.
Players
Mesenchymal lineages
Endothelial cells
Inflammatory cytokines
Sympathetic nervous system
Others
Size
Decreased endosteal Nestin-GFP+ cells Increased non-endosteal Nestin-GFP+ cells Decreased αSMA+ cells, NG2+ cells, PDGFβ+ cells
Increased overall vascular density
Decreased arterioles; shortened arteriole segments Unchanged/preserved sinusoids
Decreased transitional zone vessels
Increased small capillaries
Increased IL-1, IL-3, IL-6, TNFα, INFγ, TGFβ Increased Th+ nerve fibers
Increased megakaryocytes
Accumulation of CXCR4highCD62Llow senescent neutrophils
Functions/Mechanisms
Increased adipogenesis
Decreased osteogenic differentiation
Cellular senescence
Altered nitric oxide, urea cycle pathways
Reduced secretion of niche factors
HSC closer to non-endosteal niches, away from endosteal niches
Increased vascular leakiness Vasodilation
Decreased angiogenic potential Decreased Notch activity
HSC away from arterioles
HSC preserved in sinusoids
DLL4 regulating HSC myeloid skewing Sinusoidal Jag2 regulating HSC proliferation
IL-1β regulating HSC myeloid-skewing
IL-6 regulating megakaryocyte differentiation TNFα protecting HSC from necroptosis TGF-β regulating megakaryopoiesis
IFN regulating megakaryocytic bias
β -AR activation regulating HSC myeloid-skewing toward platelet production β2-AR inactivation regulating niche remodeling, HSC lymphoid deficiency
GFP: green fluorescent protein; αSMA: alpha smooth muscle actin; PDGFβ: platelet-derived growth factor; HSC: hematopoietic stem cells; IL: interleukin; TNFα: tumor necrosis factor alpha; INFγ: interferon gamma; TGFβ: transforming growth factor beta; DLL4: delta-like 4; Jag2: Jagged 2; AR: adrenergic receptor.
Functional switch of β adrenergic signaling (β -AR overriding β -AR) 23
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Megakaryocytes closer to sinusoids
HSC away from megakaryocytes Macrophages with impaired phagocytosis
unchanged upon aging.39 Consistent with these observa- tions, arteriole segments covered by Nestin-GFPbright cells appear shortened.38 Transitional zone vessels containing type-H endomucin (EMNC)-high endothelial cells (which are enriched in the murine trabecular BM, where they sup- port developmental bone growth71) are reduced in old mice.39,70 In contrast, small capillaries (CD31highEMCN- cells <6 mm in diameter) are notoriously expanded in the cen- tral marrow.39
The functionality of vascular endothelium declines with age, as manifested by increased vascular leakiness, increased levels of reactive oxygen species and decreased angiogenic potential.72 Poulos et al. previously reported that HSC purified from young mice and co-cultured with endothelial cells from old mice lack long-term hematopoi- etic multilineage reconstitution, while old HSC co-cul- tured with young endothelial cells maintain their self- renewal ability.72 Infusion of young endothelial cells into aged, conditioned mice revives the old hematopoietic sys- tem. Kusumbe et al. identified high Notch activity in type- H endothelial cells and their associated subendothelial/perivascular cells,70 suggesting that con- traction of endosteal vessels upon aging concomitantly occurs with impaired Notch signaling. Overexpression of the Notch ligand Dll4 in vascular endothelial cells can pre- vent myeloid skewing of hematopoietic progenitors73 but cannot completely rescue HSC aging,70 perhaps consistent with the finding of another study in which Dll4 was unchanged in the aged murine BM.40 A common finding is reduced endosteal activity of Notch ligand, since the latter study reported reduced expression of Jagged2 (Jag2) ligand in aged Nestin-GFPhigh cells. In contrast, Jag2 levels seem
increased in the sinusoids, or their associated Nestin- GFPlow cells. Moreover, Jag2 blockade induces proliferation and clustering of aged HSC near the sinusoids. Therefore, whereas the specific role of Dll4 during aging is not clear, alterations of Notch signaling do seem to be important for hematopoietic aging. Together, these results strongly sug- gest that altered Notch signaling critically contributes to HSC aging in different ways depending on the niche: in the endosteal vessels, Notch signaling appears to regulate HSC lineage commitment, whereas it is required in the sinusoids to preserve old HSC (since HSC accumulate in sinusoidal niches as a function of age).40
Inflammation
Aging of the BM microenvironment is associated with increased pro-inflammatory cytokines, both in mice and humans.74 Several lines of evidence have indicated that these inflammatory cytokines drive myeloid/megakary- ocytic differentiation. In aged-related myeloid malignan- cies, such as myeloid proliferative neoplasms and chronic myelogenous leukemia, serum interleukine (IL)-1β and IL- 6 levels are elevated.75,76 Pietras et al. reported that chronic IL-1 exposure induces HSC myeloid skewing at the expense of self-renewal.77 IL-1α/β regulates throm- bopoiesis in vitro,78,79 possibly explaining high platelet counts in aged mice.80 Defective phagocytosis of macrophages during aging induces expansion of platelet- biased HSC through Il-1β signaling.81 Il-6 promotes throm- bopoiesis either through a direct effect on BM megakaryo- cyte differentiation39 or indirectly upregulating hepatic
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