The Sympathetic Nervous System Regulates Hematopoietic Stem and Progenitor Cell Homing and Engraftment.
Authors: Lucas Daniel , Frenette Paul S. 
Published: April 2020

Abstract
The sympathetic nervous system (SNS) controls hematopoietic stem and progenitor cell (HSPC) release from their niches in the bone marrow (BM) by acting on specific niche cells: bone-lining osteoblasts during mobilization (Cell2006;124:407) and CXCL12-secreting BM stromal cells (Nature2008;452:442) in homeostasis. However, it remains unknown whether the SNS controls other processes in HSC physiology. Here, we show that an intact SNS is necessary for bone marrow reconstitution. Transplantation of lethally-irradiated recipient mice, in which the SNS was lesioned using 6-hydroxydopamine (6OHDA), with 105 healthy BM nucleated cells resulted in 65% survival of the sympathectomized mice compared to 100% survival in the control groups (6OHDA, not irradiated; Saline, not irradiated; Saline, irradiated and transplanted; p&lt;0.01, Kaplan-Meyer survival and Logrank test). Peripheral blood analyses revealed hematopoietic failure and a severe reduction in trilineage cell counts during the recovery phase. These results indicated that HSPCs engrafted with diminished efficiency in sympathectomized mice. Since donor HSPCs were obtained from intact wild-type mice the observed phenotype suggested that the SNS regulated HSPC engraftment by acting on niche cells. The observed phenotype could be due to reduced homing (i.e. the ability of HSPCs to migrate and enter the bone marrow) or to reduced proliferation of HSPC after appropriate homing. To evaluate these two possibilities, we first injected HSPCs into lethally irradiated 6OHDA-treated or control recipients and allowed the cells to migrate to the BM for 3 hours (homing assays). We found that 2.7-fold fewer donor clonogenic progenitors (CFU-C) could be detected in the BM of sympathectomized mice compared to control animals (p&lt;0.001), indicating that an intact SNS is required for HSPC homing to the bone marrow. To determine whether SNS signals are required for HSPC proliferation after homing, we evaluated the proliferative capacity of HSPCs following the administration of the cytotoxic drug 5-fluorouracyl (5FU). Mice treated with 6OHDA or control recipient mice received a single dose of 5FU (150 mg/kg) and their hematopoietic parameters and survival were monitored for 16 days. Peripheral blood analysis revealed reductions in both WBC (1.6 fold; p&lt;0.05) and RBC (1.4 fold; p&lt;0.01) in 6OHDA-treated compared to SNS-intact mice. Further analyses revealed a strong reduction (1.8 fold; p&lt;0.01) in the BM cellular content suggesting that HSPC failed to proliferate normally in 6OHDA-treated mice. The number of CFU-C and stem cell-enriched Lin−Sca1+c-kit+ (LSK) cells in the recovery phase (12 days after 5FU) were reduced 1.9-fold (p&lt;0.01). Moreover, 5FU produced a high mortality rate in the 6OHDA-lesioned group (76% survival at the end of the study; p&lt;0.05 Kaplan- Meyer survival and Logrank test) when compared to 5FU-treated SNS-intact mice (100% survival). These results suggest that HSPC require SNS signals to proliferate in response to stress to restore a functional hematopoiesis. Taken together these data indicate that the sympathetic nervous system acts on the hematopoietic stem cell niche to control both homing and proliferation in the bone marrow, two critical steps that determine the success of a bone marrow transplantation procedure.