Of Mice and Men – or a Lack of Positive Effect of Enhanced Vegetative Nervous System Tonus on Mobilization of Hematopoietic Stem and Progenitor Cells – Results in Patients with Elevated Catecholamine Level in Peripheral Blood Suffering from Acute Psychotic and Anxiety Disorders

Background. It is well known that hematopoietic stem/progenitor cells (HSPCs) circulate under steady-state conditions at detectable levels in peripheral blood (PB), with their numbers increasing in response to stress, inflammation, and tissue and organ injury. Moreover, it has been demonstrated in mice that enhanced tonus of vegetative nervous system regulates mobilization of HSPCs into PB. Moreover, UDP-galactose:ceramide galactosyltransferase-deficient mice, which exhibit aberrant nerve conduction and do not release norepinephrine (NE) into the BM microenvironment, do not mobilize HSPCs in response to G-CSF. However, as recently reported modification of sympathetic output does not affect G-CSF-induced mobilization in humans, as would be predicted. Specifically, normal human HSPC volunteer donors who were receiving NE reuptake inhibitors (NRI) for depression or β2-blockers because of hypertension mobilize in a similar manner as normal controls (Leukemia 2013; 27:24-31). Mobilization in these patients was neither enhanced by NRI administration nor suppressed by β2-blockers, as one would expect based on murine data reported in the literature.

Aim of the study. To address this intriguing issue and discrepancy between human and mice, we analyzed levels of circulating HSPCs in patients suffering from acute psychosis and anxiety disorders – clinical situations with elevated level of catecholamine in PB. Namely, these patients are under the influence of several neural mediators, and it is well known that the levels of NE and dopamine are elevated in peripheral tissues and blood.

Material and Metods. Enrolled in this study were 30 unrelated individuals with a diagnosis of the first-episode psychosis and 30 patients suffering from acute anxiety disorders. The patients were compared with an ethnic- and gender-matched control group of 35 healthy volunteers without psychiatric disorders, which were excluded according to an examination by a specialist psychiatrist. Patients with a history of serious lifetime medical events, organic brain injuries, or drug/alcohol dependence were excluded from the study. Mobilization of HSPCs was evaluated by i) FACS to enumerate the number of CD34⁺, CD133⁺, CD34⁺CD45⁺Lin^–, and CD133⁺CD45⁺Lin^– cells circulating in PB, which are enriched for HSPCs, as well as by ii) functional in vitro assays to detect the number of CFU-GM and BFU-E clonogenic progenitors circulating in PB. In parallel we measured level of adrenaline, norepinephrine (NE) and dopamine in PB serum. Both cells and catecholamine levels were enumerated in acute psychotic and anxiety disorders patients before and after treatment and compared with age- and sex-matched controls.

Results. We did not observe any significant differences in the numbers of circulating CD34⁺, CD133⁺, CD34⁺CD45⁺Lin^–, and CD133⁺CD45⁺Lin^– cells as well as clonogenic BFU-E and CFU-GM between normal controls and psychotic patients and patients with anxiety disorders. In particular number of circulating in PB HSPCs was not affected by increased level of adrenaline, norepinephrine and dopamine in PB of patients suffering from acute psychotic syndromes.

Conclusions. Our data argue against an effect of enhanced vegetative nervous system tone on the number of HSPCs circulating in PB in humans. Our negative data performed on patients suffering from acute psychoses and anxiety disorders somewhat corroborate data reported for normal HSPC volunteer donors that were previously treated with NRI because of depression or with β2-blockers because of high blood pressure and mobilized with G-CSF (Leukemia 2013; 27:24-31). This finding suggests that there are some clear differences between rodents and humans in the effect of the vegetative nervous system on HSPCs mobilization.