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Y-H. Ho and S. Méndez-Ferrer et al.
thrombopoietin levels.82 Yamashita et al. demonstrated that transient stimulation of tumor necrosis factor-α pre- vents HSC from necroptosis, and proposed that constitu- tive activation might lead to hyperproliferation of HSC and exacerbated myelopoiesis in aging and myeloprolifer- ative disorders.83 Megakaryocytes express transforming growth factor-β to regulate HSC quiescence, while megakaryocyte-derived transforming growth factor-β also stimulates thrombopoietin synthesis by BM stromal cells to enhance megakaryopoiesis.84 An elegant study by Haas et al. found that acute inflammation induces proliferation of the stem cell-like megakaryocyte progenitor to quickly replenish platelet loss, and the process is in part mediated through the interferon family.85
Despite the well-known lymphocyte deficiency associ- ated with aging, only the frequency and function (but not the absolute number of lymphoid-biased/balanced HSC) appear to decline with age.86 In fact, during aging both platelet/myeloid-biased and lymphoid-biased HSC expand, but exhibit altered gene expression programs and myeloid and platelet-skewing.80 These findings suggest a cell fate change of HSC upon aging, and the net outcome is an increase of the myeloid/platelet compartment at the expense of the lymphoid compartment. Two possible non-mutually exclusive explanations are: (i) different HSC suffer the same intrinsic abnormalities upon aging and (ii) microenvironmental alterations specifically influence HSC and direct their cell fate. In support of the second possibil- ity, distinct HSC subpopulations respond differently to inflammatory challenges during aging.87 Moreover, old lymphoid-biased/balanced HSC seem to retain normal lymphoid commitment potential when removed from an old microenvironment.5 Exogenous addition of IL-1 can block lymphocyte differentiation from old lymphoid- biased HSC, confirming the indispensable role of IL-1 in HSC fate decisions. Consistently with this notion, IL-1 blockade seems sufficient to revert the age-dependent increase of megakaryocytic-biased HSC in vitro.81 IL-1 blockade can also attenuate myeloid expansion and inflammatory arthritis associated with the elderly.88
However, whether the inflamed BM niche is the cause or the consequence of HSC aging remains debated. It is notable that mature myeloid/megakaryocytic cells are a major source of inflammatory cytokines.89 Therefore, exacerbated myelopoiesis during aging might induce myeloid/megakaryocytic HSC skewing through inflam- matory remodeling of the BM microenvironment. Many different cytokines directly affecting HSC (e.g., IL-6, tumor necrosis factor and interferon) increase during aging. A positive feedback loop between the myeloid cells and their derived inflammatory cytokines might increase both myelopoiesis and the cytokine storm. Future studies are needed to clarify the roles of other inflammatory cytokines, such as IL-6, in the regulation of HSC during aging.
Neuronal regulation by sympathetic adrenergic signaling
It has been reported that BM sympathetic stimulation of β2 or β3 adrenergic receptors (AR) regulates the egress and granulocyte – colony-stimulating factor -induced mobi- lization of HSC.90-92 A recent publication has suggested that noradrenergic nerve fibers are reduced in old murine
BM.38 The study also indicated that surgical denervation of young BM induces premature aging of the hematopoietic system, although the inflammation caused by the surgical denervation might have had a certain influence. A similar reduction of nerve fibers was found in a mouse model of an age-related blood disorder, myeloproliferative neo- plasm,75 suggesting that BM neuropathy might predispose to myeloid malignancies with age. However, a recent study did not find such a reduction of BM noradrenergic fibers in aged mice.93 Moreover, whole-mount imaging and three-dimensional reconstruction of different bones has revealed doubled BM area covered by noradrenergic nerve fibers in aged mice.39 This result is consistent with the well-known increase in sympathetic activity in the elderly, manifested for instance by an increased concentra- tion of noradrenaline in the human plasma with age.94-97 Increased sympathetic activity causes myeloid skewing of old HSC through activating β2-AR, since exacerbated thrombopoiesis is present in old wildtype mice but absent in old Adrb2-/- mice or Adrb2-/-Adrb3-/- mice.39 A previous study showed that α-AR directly regulated megakaryo- cyte migration, adhesion and proplatelet formation under stress, but α-AR did not affect the earlier commitment of progenitor cells to the megakaryocyte lineage.98 Therefore, the age-dependent increase in sympathetic innervation might activate different AR as hematopoietic progenitor cells differentiate along the megakaryocyte lineage. Additionally, the sympathetic nervous system is known to control inflammation in a context-dependent manner.99 The concentration of catecholamines and the levels of expression of different AR influence the inflammatory state of innate immune cells. Increased sympathetic activ- ity during aging might contribute to the cytokine storm by activating inflammatory cells, and subsequently affect lin- eage-bias of HSC.
Interestingly, β3-AR exhibits opposite effects on lympho- myeloid skewing, compared with β2-AR. Adult Adrb3-/- mice show a decreased frequency of endosteal lymphoid- biased HSC and/or lymphoid multipotent progenitors.38,39 Age-related remodeling of vasculature, such as reduced transitional zone vessels and expanded small capillaries, possibly explains the lymphoid deficiency in these mice.39 Altogether, these results suggest that lack of β3-AR in the microenvironment might accelerate aging of the hematopoietic system. One study suggested that adminis- tration of a β3-AR agonist to old mice rejuvenates most fea- tures of HSC aging, but overall changes of hematopoiesis in peripheral blood were not reported in this study.38 The same β3-AR agonist reduced myeloid expansion in a mouse model of myeloproliferative neoplasm75 and a murine model of Hutchinson-Gilford progeria syndrome (HGPS).39 However, hematopoietic rejuvenation was not detected in the peripheral blood of mice treated with this β3-AR ago- nist over 40 weeks in another study.75 Likewise, elderly individuals with myeloproliferative neoplasms who received a β3-AR agonist over 24 weeks did not show reju- venation in the peripheral blood counts in a human study.100 Five-month old mice lacking β3-AR reportedly showed normal peripheral blood counts39 or premature, lymphoid deficiency and myeloid skewing.38 The discrep- ancies between these studies suggest that modulating a single neuronal pathway might not be sufficient to rejuve- nate overall hematopoiesis. This may be due to the multi- ple compensatory/adjustment mechanisms of the auto- nomic nervous system revealed, for instance, in the cardio-
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haematologica | 2020; 105(1)