Aging of the Hematopoietic Stem Cell Niche: An Unnerving Matter

The drivers of aging in the hematopoietic system remain incompletely understood. In this issue of Cell Stem Cell, Ho et al., 2019Ho Y.-H. Del Toro R. Rivera-Torres J. Rak J. Korn C. García-García A. Macías D. González-Gómez C. Del Monte A. Wittner M. et al.Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging.Cell Stem Cell. 2019; 25 (this issue): 407-418Scopus (129) Google Scholar report that functional switching of β-adrenergic nerve signaling underlies remodeling of stem cell niches, driving age-associated alterations in hematopoiesis. The drivers of aging in the hematopoietic system remain incompletely understood. In this issue of Cell Stem Cell, Ho et al., 2019Ho Y.-H. Del Toro R. Rivera-Torres J. Rak J. Korn C. García-García A. Macías D. González-Gómez C. Del Monte A. Wittner M. et al.Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging.Cell Stem Cell. 2019; 25 (this issue): 407-418Scopus (129) Google Scholar report that functional switching of β-adrenergic nerve signaling underlies remodeling of stem cell niches, driving age-associated alterations in hematopoiesis. Hematopoietic aging in mice is characterized by an expansion of immunophenotypic hematopoietic stem cells (HSCs) with reduced capacity for engraftment, self-renewal, and lymphoid differentiation, resulting in myeloid-biased hematopoiesis. Hematopoietic aging is determined by both HSC intrinsic factors, such as accumulation of DNA damage, replicative stress, and autophagy, as well as extrinsic factors conferred by the endothelial and stromal micro-environment (Ergen et al., 2012Ergen A.V. Boles N.C. Goodell M.A. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing.Blood. 2012; 119: 2500-2509Crossref PubMed Scopus (175) Google Scholar, Kusumbe et al., 2016Kusumbe A.P. Ramasamy S.K. Itkin T. Mäe M.A. Langen U.H. Betsholtz C. Lapidot T. Adams R.H. Age-dependent modulation of vascular niches for haematopoietic stem cells.Nature. 2016; 532: 380-384Crossref PubMed Scopus (282) Google Scholar). However, the mechanisms and cellular components of the niche driving aging remain largely unknown. In this issue of Cell Stem Cell, Ho et al., 2019Ho Y.-H. Del Toro R. Rivera-Torres J. Rak J. Korn C. García-García A. Macías D. González-Gómez C. Del Monte A. Wittner M. et al.Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging.Cell Stem Cell. 2019; 25 (this issue): 407-418Scopus (129) Google Scholar identify disrupted β-adrenergic nerve signaling as an important determinant of niche alterations during aging that result in impaired lymphoid differentiation and myeloid expansion. Ho et al., 2019Ho Y.-H. Del Toro R. Rivera-Torres J. Rak J. Korn C. García-García A. Macías D. González-Gómez C. Del Monte A. Wittner M. et al.Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging.Cell Stem Cell. 2019; 25 (this issue): 407-418Scopus (129) Google Scholar demonstrate remodeling of stem cell niches in the bone marrow of old mice (70–100 weeks old) in comparison to young mice (age 8–30 weeks old). Niches (arterioles, transition zone vessels [TZVs], and nestin-expressing mesenchymal cells) were reduced at the endosteal surface, while capillaries and nestin-positive stromal cells expanded in non-endosteal (central) areas of the bone marrow. Niche remodeling was associated with an increase in inflammatory cytokines, such as IL1A, IL6, IFN-Ƴ, and IL3, and a clear increase in sympathetic noradrenergic nerve fibers. To explore a potential contribution of sympathetic noradrenergic signaling to the remodeling of niches and hematopoietic aging, mice deficient in β2- and/or β3-adrenergic receptors (ARs) were studied in extensive reverse transplantation experiments (to dissect niche contributions from hematopoietic cell-intrinsic effects of reduced AR signaling). Loss of adrenergic signaling in β2/β3 double knockout (DKO) mice resulted in a rescue of the aging-associated increase in megakaryopoiesis and thrombocytosis in mice. This was likely due to loss of β2-AR signaling as β2-AR signaling induced megakaryocyte differentiation and expansion via induced production of IL6 by mesenchymal cells in culture systems. However, loss of adrenergic β2/β3 signaling in DKO mice did not affect the myeloid/lymphoid skewing in the blood associated with aging. The loss of β3 signaling in β3-AR−/− mice recapitulated the reduction of TZV niches, and reduced numbers of lymphoid biased HSCs at the endosteal surface via NOS1-dependent nitric oxide production, which was established in both culture experiments and NOS1−/− mice. The distance between HSCs and megakaryocytes, an HSC niche component that regulates HSC proliferation, was increased in β3-AR−/− mice, as observed in natural aging, and is in line with a recent report (Maryanovich et al., 2018Maryanovich M. Zahalka A.H. Pierce H. Pinho S. Nakahara F. Asada N. Wei Q. Wang X. Ciero P. Xu J. et al.Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.Nat. Med. 2018; 24: 782-791Crossref PubMed Scopus (181) Google Scholar). β3-AR-deficient mice further displayed a modest and non-significant increase in immunophenotypic HSCs and myeloid-biased HSCs. Although the number of circulating myeloid and lymphoid cells did not change, megakaryocyte progenitors increased. Likewise, pharmacologic modulation using a β3-AR agonist ameliorated aging characteristics (lympho-myeloid skewing, numbers of immunophenotypic HSCs, and distance between megakaryocytes and HSCs) in the context of a mouse model of accelerated aging. HSC function was not formally interrogated in β3-AR−/− mice, but the findings complement a recent report identifying adrenergic signaling, and in particular β3-AR signaling, as an important determinant of HSC functional decline in aging via remodeling of putative HSC niches including reduced arteriolar niches and an increase in mesenchymal niches away from the endosteal region (Maryanovich et al., 2018Maryanovich M. Zahalka A.H. Pierce H. Pinho S. Nakahara F. Asada N. Wei Q. Wang X. Ciero P. Xu J. et al.Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.Nat. Med. 2018; 24: 782-791Crossref PubMed Scopus (181) Google Scholar). While the combined reports firmly relate β-adrenergic signaling to hematopoietic aging, the biological basis for the proposed disrupted β-adrenergic signaling in the aging bone marrow remains to be elucidated. In the earlier report (Maryanovich et al., 2018Maryanovich M. Zahalka A.H. Pierce H. Pinho S. Nakahara F. Asada N. Wei Q. Wang X. Ciero P. Xu J. et al.Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.Nat. Med. 2018; 24: 782-791Crossref PubMed Scopus (181) Google Scholar), aging was associated with a marked reduction in the frequency of tyrosine-hydroxylase-positive adrenergic nerve fibers in the bone marrow, suggesting that global attenuation of adrenergic signaling underlies hematopoietic aging, a notion that is supported by experiments in which denervation recapitulated the features of aging. In contrast, Ho et al., 2019Ho Y.-H. Del Toro R. Rivera-Torres J. Rak J. Korn C. García-García A. Macías D. González-Gómez C. Del Monte A. Wittner M. et al.Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging.Cell Stem Cell. 2019; 25 (this issue): 407-418Scopus (129) Google Scholar describe a significant increase in tyrosine-hydroxylase-positive adrenergic nerve fibers in the aging marrow. Their experiments reveal divergent, opposite contributions of β2 and β3 signaling to aging phenotypes. As a result, a rather complex picture emerges in which activation of β2 signaling and loss of β3 signaling may contribute to distinct features of aging hematopoiesis. A switch to β2-AR over β3-AR signaling, rather than global abrogation of adrenergic signaling, may induce niche alterations driving increased megakaryopoiesis and reduced lymphoid differentiation. Future challenging investigations will have to clarify the nature of the putative disrupted β-adrenergic signaling in aging, including assessment of nerve structures, target cells, neurotransmitter densities, and adrenergic receptor function. This would enable further investigation into the causes of these abnormalities, in which it is conceivable that inflammatory alterations in aging hematopoietic cells themselves attenuate nerve function, as demonstrated in the context of hematopoietic disease (Arranz et al., 2014Arranz L. Sánchez-Aguilera A. Martín-Pérez D. Isern J. Langa X. Tzankov A. Lundberg P. Muntión S. Tzeng Y.-S. Lai D.-M. et al.Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.Nature. 2014; 512: 78-81Crossref PubMed Scopus (304) Google Scholar), in a malicious feedforward loop. Regardless of the biological basis, the current findings substantially add to our understanding and appreciation of the contribution of the bone marrow niche to hematopoietic aging. They further establish the concept of an adrenergic-mesenchymal-hematopoietic axis directing lineage fate decisions in hematopoiesis, specifically lymphopoiesis and megakaryopoiesis. Niche signaling, in addition to HSC intrinsic wiring, determines the balance between cell lineages in the bone marrow. This notion is relevant not only in the framework of aging, but also for a more complete understanding of human pathologies, including B cell lymphopenia, often found in myeloid neoplasms and thrombocytosis in the context of myeloproliferative neoplasm. Finally, the emerging, more comprehensive picture of HSC niche alterations in aging may inform our understanding of the factors underlying clonal evolution and the predisposition for myeloid neoplasms such as MDS, MPN, and AML, the most devastating complications associated with hematopoietic aging in humans. Caution in translating findings to humans is warranted because of clear differences in the features of aging (e.g., hypocellularity and thrombocytopenia in humans versus hypercellularity and thrombocytosis in mice), but myeloid skewing and functional decline of HSCs are shared by mice and men (Rundberg Nilsson et al., 2016Rundberg Nilsson A. Soneji S. Adolfsson S. Bryder D. Pronk C.J. Human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/erythroid bias.PLoS ONE. 2016; 11: e0158369Crossref PubMed Scopus (67) Google Scholar). One might speculate that the proposed loss of arteriolar niches' redistribution of niches from the endosteum to more central areas in the bone marrow and dissociation of HSCs from megakaryocytes result in relocation of HSC to niches that may be less favorable to the protection of their genetic integrity, quiescence, and maintenance. Although it is unknown whether perivascular niches in different regions of the bone marrow are functionally distinct, megakaryocytes are involved in maintenance by regulating quiescence (Bruns et al., 2014Bruns I. Lucas D. Pinho S. Ahmed J. Lambert M.P. Kunisaki Y. Scheiermann C. Schiff L. Poncz M. Bergman A. Frenette P.S. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion.Nat. Med. 2014; 20: 1315-1320Crossref PubMed Scopus (400) Google Scholar), and dissociation may contribute to increased HSC proliferation and DNA damage, well-documented features of HSC aging (Beerman et al., 2014Beerman I. Seita J. Inlay M.A. Weissman I.L. Rossi D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle.Cell Stem Cell. 2014; 15: 37-50Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). Replicative stress and DNA damage may be exacerbated by an increase in inflammatory niche signaling (Zambetti et al., 2016Zambetti N.A. Ping Z. Chen S. Kenswil K.J.G. Mylona M.A. Sanders M.A. Hoogenboezem R.M. Bindels E.M.J. Adisty M.N. Van Strien P.M.H. et al.Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia.Cell Stem Cell. 2016; 19: 613-627Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar) induced by disturbed adrenergic signaling to mesenchymal niches, ultimately resulting in the selection of genetic clones resistant to this replicative and genotoxic stress associated with a new environment (Figure 1). The exciting possibility of pharmacologic revitalization of aging niches, e.g., by β3-AR agonists (Ho et al., 2019Ho Y.-H. Del Toro R. Rivera-Torres J. Rak J. Korn C. García-García A. Macías D. González-Gómez C. Del Monte A. Wittner M. et al.Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging.Cell Stem Cell. 2019; 25 (this issue): 407-418Scopus (129) Google Scholar, Maryanovich et al., 2018Maryanovich M. Zahalka A.H. Pierce H. Pinho S. Nakahara F. Asada N. Wei Q. Wang X. Ciero P. Xu J. et al.Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.Nat. Med. 2018; 24: 782-791Crossref PubMed Scopus (181) Google Scholar), prompts further experimental exploration of such potential links between remodeling of HSC niches and clonal evolution. Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological AgingHo et al.Cell Stem CellJuly 11, 2019In BriefRecent studies have suggested a microenvironmental contribution to stem-cell aging, but the mechanisms are largely unexplored. Méndez-Ferrer et al. report anatomical remodeling of blood-stem-cell-supporting niches and functional switch of β adrenergic signals, leading to myeloid expansion during aging. Targeting the microenvironment can improve pathological, premature, niche-dependent hematopoietic aging in mice. Full-Text PDF Open Access