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