Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration

Anti-cancer chemotherapy drugs challenge hematopoietic tissues to regenerate, but commonly produce long-term sequelae. Deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating chemotherapy-induced hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes significant sensory neuropathy. Here, we demonstrate that chemotherapy-induced nerve injury in the bone marrow is a critical lesion impairing hematopoietic regeneration. We show using various pharmacological and genetic models that the selective loss of adrenergic innervation in the BM alters its regeneration following genotoxic insult. Sympathetic nerves in the marrow promote the survival of stem cell niche constituents that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuro-regeneration using 4-methylcatechol or glial-derived neurotrophic factor (GDNF) administration can restore hematopoietic recovery. Thus, these results shed light on the potential benefit of adrenergic nerve protection to shield hematopoietic niches from injury.