Sympathetic Nerves Stimulate Bone Marrow Function After Chemotherapy

Chemotherapy often results in acute bone marrow cytotoxicity and chronic defects in hematopoietic stem cell (HSC) function, but the mechanisms by which chemotherapy promotes hematopoietic dysregulation are unknown. Recent studies have implicated the sympathetic nervous system (SNS), which is also damaged by a subset of chemotherapeutic drugs, in HSC migration from the bone marrow, prompting Lucas and colleagues to hypothesize that chemotherapy-induced nerve damage impairs bone marrow regeneration. Mice treated with cisplatin, a neurotoxic chemotherapeutic, exhibited reduced HSC reconstitution after bone marrow transplantation, which was associated with loss of SNS fibers in the bone marrow. Moreover, specific depletion of sympathetic neurons delayed hematopoietic recovery after irradiation or 5-fluorouracil treatment, suggesting that the SNS is required for HSC expansion and survival after injury. This prosurvival effect was dependent on signaling through β2- and β3-adrenergic receptors and SNS-mediated protection of nestin-positive cells and endothelial cells in the bone marrow stem cell niche in response to genotoxic insult. In addition, cisplatin-induced SNS neuropathy diminished HSC mobilization from the bone marrow into the blood in response to granulocyte colony-stimulating factor (G-CSF). These defects in bone marrow function were rescued by deletion of p53 in the peripheral sympathetic neurons of cisplatin-treated mice, which enhanced the survival of these cells and restored hematopoietic regeneration after transplantation. Furthermore, administration of neuroprotective agents, including glial-derived neurotrophic factor or 4-methylcatechol, decreased cisplatin-induced sympathetic nerve damage, increased the survival of niche cells, and restored G-CSF–driven HSC mobilization, resulting in accelerated bone marrow recovery and increased survival following genotoxic insult or SNS denervation. These results show that chemotherapy-induced injury of sympathetic nerves in the bone marrow prevents hematopoietic recovery and suggest that treatment with neuroprotective drugs during chemotherapy may preserve HSC function and reduce long-term bone marrow injury.

Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med 2013 May 5 [Epub ahead of print].