Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration

Nature Medicine volume 19, pages 695–703 (2013)Cite this article

Subjects

Abstract

Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Neurotoxic chemotherapy induces bone marrow SNS injury and reduces engraftment after transplantation.
Figure 2: The SNS regulates bone marrow recovery.
Figure 3: Reduced bone marrow recovery after cisplatin chemotherapy is due to SNS injury.
Figure 4: β-adrenergic signals protect the niche from genotoxic insult.
Figure 5: Bone marrow SNS injury impairs progenitor mobilization.
Figure 6: Neuroprotection restores normal bone marrow engraftment and mobilization.

Similar content being viewed by others

References

  1. Hooper, A.T. et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4, 263–274 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Banfi, A. et al. High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post–bone marrow transplantation osteopenia. Cancer 92, 2419–2428 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Dominici, M. et al. Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood 114, 2333–2343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mauch, P. et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 31, 1319–1339 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Haas, R. et al. Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma. Blood 83, 3787–3794 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Tricot, G. et al. Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood 85, 588–596 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Robinson, S.N., Freedman, A.S., Neuberg, D.S., Nadler, L.M. & Mauch, P.M. Loss of marrow reserve from dose-intensified chemotherapy results in impaired hematopoietic reconstitution after autologous transplantation: CD34+, CD34+38−, and week-6 CAFC assays predict poor engraftment. Exp. Hematol. 28, 1325–1333 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Perseghin, P. et al. Management of poor peripheral blood stem cell mobilization: incidence, predictive factors, alternative strategies and outcome. A retrospective analysis on 2177 patients from three major Italian institutions. Transfus. Apher. Sci. 41, 33–37 (2009).

    Article  PubMed  Google Scholar 

  9. Noach, E.J. et al. Chemotherapy prior to autologous bone marrow transplantation impairs long-term engraftment in mice. Exp. Hematol. 31, 528–534 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Galotto, M. et al. Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients. Exp. Hematol. 27, 1460–1466 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Kemp, K. et al. Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy. Ann. Hematol. 89, 701–713 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Cavaletti, G. & Marmiroli, P. Chemotherapy-induced peripheral neurotoxicity. Nat. Rev. Neurol. 6, 657–666 (2010).

    Article  PubMed  Google Scholar 

  15. Aloe, L., Manni, L., Properzi, F., De Santis, S. & Fiore, M. Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis. Auton. Neurosci. 86, 84–93 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Lapidot, T., Dar, A. & Kollet, O. How do stem cells find their way home? Blood 106, 1901–1910 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Savitt, J.M., Jang, S.S., Mu, W., Dawson, V.L. & Dawson, T.M. Bcl-x is required for proper development of the mouse substantia nigra. J. Neurosci. 25, 6721–6728 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Spiegel, A. et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat. Immunol. 8, 1123–1131 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Trimmer, P.A., Smith, T.S., Jung, A.B. & Bennett, J.P. Jr. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 5, 233–239 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kobayashi, H. et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12, 1046–1056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ding, L., Saunders, T.L., Enikolopov, G. & Morrison, S.J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lévesque, J.P. et al. Mobilization by either cyclophosphamide or granulocyte colony-stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp. Hematol. 30, 440–449 (2002).

    Article  PubMed  Google Scholar 

  27. Schober, A. et al. Glial cell line–derived neurotrophic factor rescues target-deprived sympathetic spinal cord neurons but requires transforming growth factor-β as cofactor in vivo. J. Neurosci. 19, 2008–2015 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Saita, K. et al. A catechol derivative (4-methylcatechol) accelerates the recovery from experimental acrylamide-induced neuropathy. J. Pharmacol. Exp. Ther. 276, 231–237 (1996).

    CAS  PubMed  Google Scholar 

  29. Callizot, N. et al. Interleukin-6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity. Cancer Chemother. Pharmacol. 62, 995–1007 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Smeyne, R.J. et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368, 246–249 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Crowley, C. et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76, 1001–1011 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Rezaee, F. et al. Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway. PLoS ONE 5, e9690 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Coppola, V. et al. Ablation of TrkA function in the immune system causes B cell abnormalities. Development 131, 5185–5195 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Kiel, M.J., Yilmaz, O.H., Iwashita, T., Terhorst, C. & Morrison, S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Omatsu, Y. et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Frenette, P.S., Pinho, S., Lucas, D. & Scheiermann, C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu. Rev. Immunol. 31, 285–316 (2013).

    Article  PubMed  Google Scholar 

  37. Yamazaki, K. & Allen, T.D. Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the “neuro-reticular complex”. Am. J. Anat. 187, 261–276 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Presley, C.A. et al. Bone marrow connexin-43 expression is critical for hematopoietic regeneration after chemotherapy. Cell Commun. Adhes. 12, 307–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Franco, M., Roswall, P., Cortez, E., Hanahan, D. & Pietras, K. Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 118, 2906–2917 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Windebank, A.J. & Grisold, W. Chemotherapy-induced neuropathy. J. Peripher. Nerv. Syst. 13, 27–46 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Chruscinski, A.J. et al. Targeted disruption of the β2 adrenergic receptor gene. J. Biol. Chem. 274, 16694–16700 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Mignone, J.L., Kukekov, V., Chiang, A.S., Steindler, D. & Enikolopov, G. Neural stem and progenitor cells in nestin-GFP transgenic mice. J. Comp. Neurol. 469, 311–324 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Lucas, D., Battista, M., Shi, P.A., Isola, L. & Frenette, P.S. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3, 364–366 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kamei, J., Nozaki, C. & Saitoh, A. Effect of mexiletine on vincristine-induced painful neuropathy in mice. Eur. J. Pharmacol. 536, 123–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Miller, C.L., Dykstra, B. & Eaves, C.J. Characterization of mouse hematopoietic stem and progenitor cells. Curr. Protoc. Immunol. 80, 22B.2 (2008).

    Google Scholar 

  47. Yuan, R., Astle, C.M., Chen, J. & Harrison, D.E. Genetic regulation of hematopoietic stem cell exhaustion during development and growth. Exp. Hematol. 33, 243–250 (2005).

    Article  PubMed  Google Scholar 

  48. Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank C. Prophete, M. Huggins and N. Dholakia for technical assistance. We thank K. Ito for helpful discussions. We thank G. Karsenty (Columbia University) for providing Adrb2tm1Bkk/J mice and A. Ting (Mount Sinai School of Medicine) for the PCL5.1neg plasmid. This work was supported by the US National Institutes of Health to P.S.F. (NIH; R01 grants DK056638 and HL069438). D.L. was a fellow of Fundación Ramón Areces. C.S. was supported by a fellowship from the German Academic Exchange Service (DAAD). A.C. is funded by a fellowship from the NIH National Heart, Lung and Blood Institute (NHLBI; 5F30HL099028-02). I.B. was the recipient of an American Society of Hematology–European Hematology Association (ASH-EHA) research exchange award. Y.K. was supported by the Japan Society for the Promotion of Science (JSPS). C.B. and L.T. are supported by the NIH intramural research program, Center for Cancer Research, NCI.

Author information

Author notes

  1. Christoph Scheiermann

    Present address: Present address: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.,

Authors and Affiliations

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

    Daniel Lucas, Christoph Scheiermann, Andrew Chow, Yuya Kunisaki, Ingmar Bruns & Paul S Frenette

  2. Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

    Andrew Chow & Paul S Frenette

  3. Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Dusseldorf, Germany

    Ingmar Bruns

  4. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)-Frederick, Frederick, Maryland, USA

    Colleen Barrick & Lino Tessarollo

Authors
  1. Daniel Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christoph Scheiermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuya Kunisaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ingmar Bruns
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Colleen Barrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lino Tessarollo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul S Frenette
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.L. designed and performed experiments and wrote the paper. C.S., A.C., I.B. and Y.K. performed experiments and analyzed data. P.S.F. designed experiments and wrote the paper. C.B. and L.T. generated and provided Ta1-Cre:Ntrk1neo/neo mice.

Corresponding author

Correspondence to Paul S Frenette.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–19 and Supplementary Tables 1–7 (PDF 12055 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lucas, D., Scheiermann, C., Chow, A. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med 19, 695–703 (2013). https://doi.org/10.1038/nm.3155

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3155

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research