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Niche alterations promoting hematopoietic aging
vascular system.101 It is worth mentioning that myeloid and lymphoid cells are also a source of catecholamines.102 Adrenal gland-derived adrenaline and immune cell-derived (nor)adrenaline might contribute to increased levels of adrenaline and noradrenaline in the circulation of aged individuals94-97 which, together with the increased BM noradrenergic innervation, might activate BM AR. We pro- pose that sympathetic regulation of lympho-myeloid skewing pivots on activation or inactivation of different AR. A functional switch of neurotransmission (β2-AR over- riding β3-AR) with age, rather than a general decline of BM noradrenergic innervation,38 might initiate BM niche remodeling and subsequently promote HSC myeloid skewing toward platelet production. Further investigation of other adrenergic and/or cholinergic signaling pathways possibly influencing aging is warranted.
Other players in the bone marrow microenvironment
Emerging data suggest that the progeny of HSC can feed back to regulate their activity under homeostasis, raising the possibility that mature hematopoietic cells (or their interactions with others) also contribute to HSC aging. For instance, clearance of senescent CD62LlowCXCR4high neu- trophils by macrophages has been reported to modulate HSC niches.103 Frisch et al. discovered that aged macrophages are unable to engulf senescent neutrophils, leading to expansion of megakaryocytic-biased HSC through IL-1β signaling.81 Another key player is the megakaryocyte, reportedly expressing CXCL4, throm- bopoietin and transforming growth factor-β to control HSC proliferation/quiescence.32-34 In murine BM, around 20% of HSC are spatially associated with megakaryo- cytes,32 and depletion of megakaryocytes expands platelet- biased HSC.35 During aging, megakaryocytes are found in increased numbers, lodging closer to sinusoids, and abun- dantly forming pseudopodial extensions (likely to be pro- platelets).39 Of note, the distance between HSC and megakaryocytes increases substantially,38,39 suggesting a remodeling of megakaryocyte niches with age. It is possi- ble that megakaryocytes with these morphological changes fail to anchor HSC, inducing HSC hyperprolifera- tion and lineage bias. However, whether and how age- related alterations of megakaryocytes regulate HSC aging is still unknown and requires further investigation.
Premature aging in Hutchinson-Gilford progeria syndrome
In HGPS, aberrant splicing of the LMNA gene (encoding lamin A and C) leads to nuclear assembly of the truncated protein, prelamin A (progerin).104,105 Certain hallmarks of murine hematopoietic aging, such as increased platelet counts, have been observed in HGPS.106 Given that cells aging naturally also express increased levels of progerin,107 it is possible that normal physiological conditions and progeria might share some aging mechanisms. Grigoryan et al. recently reported that HSC deficient of LMNA dis- play a premature aging-like phenotype,108 suggesting a prominent role of lamin A/C in hematopoiesis at the level of HSC. The strong impact of progeria on growth and sex- ual maturation might be paralleled by altered endocrine regulation of HSC, since growth hormones and sex hor- mones regulate HSC survival, proliferation and lineage commitment.109-112 However, it remains unknown whether
premature hematopoietic aging in HGPS is a consequence of progerin accumulation in HSC, other hematopoietic cells and/or the microenvironment. Using the LmnaG609G/G609G mouse model,113 we found that primary LmnaG609G/G609G mice exhibit features of premature hematopoietic aging; however, premature hematopoietic aging is not observed in wildtype recipients carrying LmnaG609G/G609G hematopoietic cells.39 Microenvironmental alterations are observed in LmnaG609G/G609G mice, some of which are shared between normally aged mice, such as elevated levels of pro-inflammatory cytokines (IL-3, IL-6, IL-1, interferon-γ), increased megakaryocytes with pro- platelet-like structure and megakaryocyte apposition to BM sinusoids. Of note, β3-AR agonism improves exacer- bated myeloid expansion and restores the apposition of HSC to megakaryocytes. These results suggest that pre- mature hematopoietic aging in HGPS is not HSC- autonomous, and certain aging features can be rejuvenat- ed by targeting the microenvironment.39
Aged hematopoietic stem cells/ microenvironment: chicken or egg?
One remaining key question relates to whether microenvironmental alterations initiate HSC aging and/or whether old HSC cause niche remodeling. It is notewor- thy that HSC aging is not characterized by a single cellular feature, and different aging features might emerge individ- ually at different developmental stages. For instance, in murine aging, defective lymphopoiesis starts early, at the age of 8 months old,114 while increased platelet counts do not seem to be pronounced until 18 months.39 BM nor- adrenergic nerve fibers appear to be decreased in adult, 8- month old mice75 (Supplementary Figure 5B in the report of that study), but these fibers appear increased in aged (20-month old) mice, when β3-AR signaling is already strongly reduced.39 A deficiency in β3-AR accelerates the loss of endosteal lymphoid-biased HSC in 4-month old mice, but it does not aggravate HSC aging in old mice.39 In contrast, a deficiency in β2-AR impairs megakaryopoiesis in young and old mice, and double knockout mice for β2- AR and β3-AR recapitulate the hematopoietic phenotype of single β2-AR-deficient mice. These results suggest that β2-AR overrides β3-AR during aging, and that this adrener- gic remodeling contributes to imbalanced lymphoid/myeloid output. We propose that a lack of β3- AR activity near endosteum initiates the contraction of endosteal niches, which attenuates lymphopoiesis, favors myeloid bias and pushes HSC away from the endosteum. An adrenergic switch from β3-AR to β2-AR could feed back to worsen the reduction of endosteal niches, since activa- tion of β2-AR on osteoblasts is known to restrain bone for- mation.115 However, the cell types expressing β2-AR and/or β3-AR involved in aged hematopoiesis are still elusive. Chances are that cells highly expressing β2-AR replace those with high expression of β3-AR over time, or BM niche cells ubiquitously increase β2-AR while decreasing β3-AR upon aging. These and other hypotheses need to be validated in future studies116 since the experiments were performed using global knockouts. Tissue-specific dele- tion of β2-AR and/or β3-AR will provide further insights into the mechanisms of β-adrenergic switching during aging. Importantly, β2-AR and β3-AR have different affini- ties for noradrenaline and adrenaline; whereas β3-AR
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