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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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).

Author information

Author notes

    • Noboru Asada

    Present address: Okayama University Hospital, Department of Hematology and Oncology, Okayama, Japan

  1. These authors contributed equally: Ali H. Zahalka, Halley Pierce.

Affiliations

  1. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY, USA

    • Maria Maryanovich
    • , Ali H. Zahalka
    • , Halley Pierce
    • , Sandra Pinho
    • , Fumio Nakahara
    • , Noboru Asada
    • , Qiaozhi Wei
    • , Xizhe Wang
    • , Paul Ciero
    •  & Paul S. Frenette
  2. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    • Maria Maryanovich
    • , Ali H. Zahalka
    • , Halley Pierce
    • , Sandra Pinho
    • , Fumio Nakahara
    • , Noboru Asada
    • , Qiaozhi Wei
    • , Xizhe Wang
    • , Paul Ciero
    •  & Paul S. Frenette
  3. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    • Sandra Pinho
    •  & Paul S. Frenette
  4. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Jianing Xu
  5. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Avigdor Leftin

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul S. Frenette.

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https://doi.org/10.1038/s41591-018-0030-x