Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration

Daniel Lucas, Christoph Scheiermann, Andrew Chow, Yuya Kunisaki, Ingmar Bruns, Colleen Barrick, Lino Tessarollo, Paul S. Frenette

Research output: Contribution to journalArticle

129 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)695-703
Number of pages9
JournalNature Medicine
Volume19
Issue number6
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Lucas, D., Scheiermann, C., Chow, A., Kunisaki, Y., Bruns, I., Barrick, C., Tessarollo, L., & Frenette, P. S. (2013). Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nature Medicine, 19(6), 695-703. https://doi.org/10.1038/nm.3155