Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multilineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor β3 signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging. Strikingly, supplementation of a sympathomimetic acting selectively on adrenoreceptor β3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.
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López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Signer, R. A. J. & Morrison, S. J. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell 12, 152–165 (2013).
Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).
Guidi, N. & Geiger, H. Rejuvenation of aged hematopoietic stem cells. Semin. Hematol. 54, 51–55 (2017).
Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017).
Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).
Mohrin, M. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).
Norddahl, G. L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8, 499–510 (2011).
Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).
Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014).
Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl. Acad. Sci. USA 102, 9194–9199 (2005).
Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).
Beerman, 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 15, 37–50 (2014).
Moehrle, B. M. et al. Stem cell-specific mechanisms ensure genomic fidelity within HSCs and upon aging of HSCs. Cell Rep. 13, 2412–2424 (2015).
Beerman, I. & Rossi, D. J. Epigenetic regulation of hematopoietic stem cell aging. Exp. Cell Res. 329, 192–199 (2014).
Florian, M. C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012).
Kusumbe, A. P. et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature 532, 380–384 (2016).
Guidi, N. et al. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J. 36, 840–853 (2017).
Poulos, M. G. et al. Endothelial transplantation rejuvenates aged hematopoietic stem cell function. J. Clin. Invest. 127, 4163–4178 (2017).
Ergen, A. V., Boles, N. C. & Goodell, M. A. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119, 2500–2509 (2012).
Tuljapurkar, S. R. et al. Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging. J. Anat. 219, 574–581 (2011).
Mendelson, A. & Frenette, P. S. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat. Med. 20, 833–846 (2014).
Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).
Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013).
Ding, L. & Morrison, S. J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).
Itkin, T. et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532, 323–328 (2016).
Bruns, I. et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20, 1315–1320 (2014).
Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).
Yamazaki, S. et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2011).
Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).
Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).
Maestroni, G. J. et al. Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp. Hematol. 26, 1172–1177 (1998).
Méndez-Ferrer, S., Battista, M. & Frenette, P. S. Cooperation of β(2)- and β(3)-adrenergic receptors in hematopoietic progenitor cell mobilization. Ann. NY Acad. Sci. 1192, 139–144 (2010).
Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).
Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695–703 (2013).
Zhao, M. et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20, 1321–1326 (2014).
Hanoun, M. et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15, 365–375 (2014).
Arranz, L. et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512, 78–81 (2014).
Thiel, G. & Synapsin, I. synapsin II, and synaptophysin: marker proteins of synaptic vesicles. Brain Pathol. 3, 87–95 (1993).
Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
Levi-Montalcini, R. The nerve growth factor 35 years later. Science 237, 1154–1162 (1987).
Pinho, S. et al. PDGFRα and CD51 mark human nestin+sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J. Exp. Med. 210, 1351–1367 (2013).
Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784.e6 (2017).
Young, K. et al. Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging. J. Exp. Med. 213, 2259–2267 (2016).
Afan, A. M., Broome, C. S., Nicholls, S. E., Whetton, A. D. & Miyan, J. A. Bone marrow innervation regulates cellular retention in the murine haemopoietic system. Br. J. Haematol. 98, 569–577 (1997).
Miyan, J. A., Broome, C. S. & Whetton, A. D. Neural regulation of bone marrow. Blood 92, 2971–2973 (1998).
Gekas, C. & Graf, T. CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age. Blood 121, 4463–4472 (2013).
Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).
Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A. & Weissman, I. L. The aging of hematopoietic stem cells. Nat. Med. 2, 1011–1016 (1996).
Rinkevich, Y. et al. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration. Proc. Natl. Acad. Sci. USA 111, 9846–9851 (2014).
Benestad, H. B., Strøm-Gundersen, I., Iversen, P. O., Haug, E. & Njâ, A. No neuronal regulation of murine bone marrow function. Blood 91, 1280–1287 (1998).
Cabezas-Wallscheid, N. et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 15, 507–522 (2014).
Asada, N. et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat. Cell Biol. 19, 214–223 (2017).
van der Maaten, L. & Hinton, G. Visualizing data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).
Kowalczyk, M. S. et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res. 25, 1860–1872 (2015).
Xing, Z. et al. Increased hematopoietic stem cell mobilization in aged mice. Blood 108, 2190–2197 (2006).
Geiger, H., Koehler, A. & Gunzer, M. Stem cells, aging, niche, adhesion and Cdc42: a model for changes in cell-cell interactions and hematopoietic stem cell aging. Cell Cycle 6, 884–887 (2007).
Liang, Y., Van Zant, G. & Szilvassy, S. J. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106, 1479–1487 (2005).
Bellinger, D. L. et al. Age-related alterations in autonomic nervous system innervation of lymphoid tissue. in Handbook of Neurochemistry and Molecular Neurobiology: Neuroimmunology (eds. Lajtha, A., Galoyan, A. & Besedovsky, H. O.) 61–81 (Springer US, Boston, MA, 2008).
Pierce, H. et al. Cholinergic signals from the CNS regulate G-CSF-mediated HSC mobilization from bone marrow via a glucocorticoid signaling relay. Cell Stem Cell 20, 648–658.e4 (2017).
Kawamoto, T. & Shimizu, M. A method for preparing 2- to 50-micron-thick fresh-frozen sections of large samples and undecalcified hard tissues. Histochem. Cell Biol. 113, 331–339 (2000).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).
Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
We thank J. Vijg (Department of Genetics, Albert Einstein College of Medicine) for advice on experiment design and for providing old C57BL/6 mice for initial experiments. We also thank C. Prophete for technical assistance, M. Lee for assistance with old mice, and D. Sun and L. Tesfa for assistance with cell sorting and S. Maqbool for RNA sequencing. We are also grateful to the New York State Department of Health (NYSTEM Program) for shared facility (C029154) and research support (N13G-262) and the Leukemia and Lymphoma Society’s Translational Research Program. This work was supported by R01 or U01 grants from the National Institutes of Health (NIH) (DK112976, DK056638, HL116340, HL097819, and DK116312 to P.S.F.) and by the New York Stem Cell Foundation (NYSCF). M.M. is a New York Stem Cell Foundation (NYSCF) Druckenmiller fellow and was previously supported by the EMBO European Commission FP7 (Marie Curie Actions; EMBOCOFUND2012, GA-2012-600394, ALTF 447-2014). A.H.Z was supported by NIH Training Grant (T32 NS007098) and by a National Cancer Institute (NCI) predoctoral M.D./Ph.D. fellowship (F30 CA203446). F.N. and N.A. were supported by the Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science (JSPS). A.L is supported by NCI Individual Postdoctoral Fellowship (F32), Ruth L. Kirschstein National Research Service Award (NCI 1F32CA20277).
The authors declare no competing financial interests.
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Maryanovich, M., Zahalka, A.H., Pierce, H. et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med 24, 782–791 (2018). https://doi.org/10.1038/s41591-018-0030-x
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