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Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche

An Author Correction to this article was published on 22 March 2019

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Abstract

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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Fig. 1: Aging induces remodeling of the HSC niche.
Fig. 2: Aging induces the loss of niche-associated adrenergic nerves.
Fig. 3: Aging expands MSCs and reduces their HSC maintenance activity.
Fig. 4: Surgical denervation of young BM induces premature HSC and niche aging.
Fig. 5: ADRβ3 signaling is essential for maintenance of aging HSCs.

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Change history

  • 22 March 2019

    In the version of this article originally published, the key for Fig. 4c was incorrect. The symbols for ‘Sham’ and ‘Den’ were reversed. The error has been corrected in the PDF and HTML versions of the manuscript.

References

  1. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  Google Scholar 

  2. Signer, R. A. J. & Morrison, S. J. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell 12, 152–165 (2013).

    Article  CAS  Google Scholar 

  3. Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    Article  CAS  Google Scholar 

  4. Guidi, N. & Geiger, H. Rejuvenation of aged hematopoietic stem cells. Semin. Hematol. 54, 51–55 (2017).

    Article  Google Scholar 

  5. Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017).

    Article  CAS  Google Scholar 

  6. Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. Mohrin, M. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).

    Article  CAS  Google Scholar 

  10. Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014).

    Article  CAS  Google Scholar 

  11. Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl. Acad. Sci. USA 102, 9194–9199 (2005).

    Article  CAS  Google Scholar 

  12. Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Beerman, I. & Rossi, D. J. Epigenetic regulation of hematopoietic stem cell aging. Exp. Cell Res. 329, 192–199 (2014).

    Article  CAS  Google Scholar 

  16. Florian, M. C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012).

    Article  CAS  Google Scholar 

  17. Kusumbe, A. P. et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature 532, 380–384 (2016).

    Article  CAS  Google Scholar 

  18. Guidi, N. et al. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J. 36, 840–853 (2017).

    Article  CAS  Google Scholar 

  19. Poulos, M. G. et al. Endothelial transplantation rejuvenates aged hematopoietic stem cell function. J. Clin. Invest. 127, 4163–4178 (2017).

    Article  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Mendelson, A. & Frenette, P. S. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat. Med. 20, 833–846 (2014).

    Article  CAS  Google Scholar 

  23. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    Article  Google Scholar 

  24. Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013).

    Article  CAS  Google Scholar 

  25. Ding, L. & Morrison, S. J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).

    Article  CAS  Google Scholar 

  26. Itkin, T. et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532, 323–328 (2016).

    Article  CAS  Google Scholar 

  27. Bruns, I. et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20, 1315–1320 (2014).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Yamazaki, S. et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2011).

    Article  CAS  Google Scholar 

  30. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

    Article  CAS  Google Scholar 

  31. Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    Article  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. 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).

    Article  Google Scholar 

  34. Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).

    Article  CAS  Google Scholar 

  35. Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695–703 (2013).

    Article  CAS  Google Scholar 

  36. Zhao, M. et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20, 1321–1326 (2014).

    Article  CAS  Google Scholar 

  37. 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).

    Article  CAS  Google Scholar 

  38. Arranz, L. et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512, 78–81 (2014).

    Article  CAS  Google Scholar 

  39. Thiel, G. & Synapsin, I. synapsin II, and synaptophysin: marker proteins of synaptic vesicles. Brain Pathol. 3, 87–95 (1993).

    Article  CAS  Google Scholar 

  40. Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).

    Article  Google Scholar 

  41. Levi-Montalcini, R. The nerve growth factor 35 years later. Science 237, 1154–1162 (1987).

    Article  CAS  Google Scholar 

  42. 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).

    Article  CAS  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. Young, K. et al. Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging. J. Exp. Med. 213, 2259–2267 (2016).

    Article  CAS  Google Scholar 

  45. 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).

    Article  CAS  Google Scholar 

  46. Miyan, J. A., Broome, C. S. & Whetton, A. D. Neural regulation of bone marrow. Blood 92, 2971–2973 (1998).

    CAS  PubMed  Google Scholar 

  47. Gekas, C. & Graf, T. CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age. Blood 121, 4463–4472 (2013).

    Article  CAS  Google Scholar 

  48. Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).

    Article  CAS  Google Scholar 

  49. 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).

    Article  CAS  Google Scholar 

  50. 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).

    Article  CAS  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  Google Scholar 

  53. Asada, N. et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat. Cell Biol. 19, 214–223 (2017).

    Article  CAS  Google Scholar 

  54. van der Maaten, L. & Hinton, G. Visualizing data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).

    Google Scholar 

  55. 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).

    Article  CAS  Google Scholar 

  56. Xing, Z. et al. Increased hematopoietic stem cell mobilization in aged mice. Blood 108, 2190–2197 (2006).

    Article  CAS  Google Scholar 

  57. 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).

    Article  CAS  Google Scholar 

  58. 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).

    Article  CAS  Google Scholar 

  59. 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).

  60. 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).

    Article  CAS  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  Google Scholar 

  63. 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).

    Article  CAS  Google Scholar 

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Acknowledgements

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).

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M.M. designed the study, performed most of the experiments, and analyzed data; A.H.Z. advised on experiment design, developed and performed denervation surgeries, imaged and quantified prostate innervation, and helped with Alzet pump implantations. H.P. advised on experiment design, performed blood CFU-C experiments and helped with bone marrow transplantations and Alzet pump implantations. S.P. advised on experiment design and helped with HSC transplantations. F.N. helped with sorting and with CFU-F and mesensphere cultures. N.A. helped with HSC imaging and quantification of HSC distributions. Q.W. and J.X. analyzed RNA-seq data. X.W. and P.C. helped with experiments. A.L. helped with image quantification analysis. P.S.F supervised the study. M.M and P.S.F interpreted data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Paul S. Frenette.

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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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