Sympathetic Neuropathy and the Development of Myeloproliferative Neoplasms

Sympathetic neuropathy & myeloproliferative neoplasm

A study published in the August 07, 2014 issue of Nature magazine reveals that an impaired neuro-endocrine microenvironment of the bone marrow, and particularly the sympathetic neuropathy play a crucial role in the development and clinical outcome of myeloproliferative neoplasms (MPNs).

This and related studies may represent a breakthrough in hematology research and a paradigm shift in the MPNs’ therapeutic strategies. Interestingly, an increasing number of studies indicate that a dysfunctional brain-bone marrow communication may contribute to the pathogenesis of some common human diseases.

Innervation of bone marrow occurs late in fetal life, just before the onset of hemopoietic activity. Nerves enter the marrow accompanying arteries, travel with the vascular plexuses deep in the marrow, arborize in surrounding parenchyma, and end among hemato- and lymphopoietic cells. In the bone marrow, a close association between catecholamine-, glutamate-, or peptide-containing nerve fibers and osteoblasts or osteoclasts in the endosteum is often observed.

Circadian oscillations and the cyclical release of hematopoietic stem cells (HSCs) are regulated through circadian norepinephrine (noradrenaline) secretion by the sympathetic nervous system (SNS).

These noradrenergic signals, locally delivered by sympathetic nerves in the bone marrow are transmitted to stromal cells by the β₃-adrenergic receptor (Méndez-Ferrer S et al., Nature, 2008; 452:442). Recent evidence indicates that signals from the SNS modify the activity of the hematopoietic niche, acting as regulators of the mobilization of hematopoietic progenitors (Katayama Y et al., Cell, 2006, 124:407).

In the Nature study Lorena Arranz and colleagues from the Stem Cell Physiopathology Group at the Spanish National Cardiovascular Research Center, Madrid, Spain demonstrate a sympathetic neuropathy and that the neuroendocrine-immune mechanisms regulating the hematopoietic niche are impaired in MPN.

They provide evidence that in the bone marrow the overproduction of interleukin-1β by mutant progenitors can damage the Schwann cells that usually protect sympathetic nerve endings. This neuro‐glial damage enhances the susceptibility of mesenchymal stem cells (MSC) in the haematopoietic niche to cell death caused by mutant haematopoietic cells.

Thus, the authors report that the sympathetic nerve fibers, the supporting Schwann cells and MSCs are reduced in the bone marrow of MPN patients. Of note, administration of neuroprotective or sympathomimetic drugs such as β₃-adrenergic agonists prevented mutant HSC expansion and MPN progression.

Currently, the only real cure available for MPN is a bone marrow transplant, which may not be advisable in some patients such as the elderly. This study may open the door to exploring a broader arsenal of therapeutic approaches in MPN.

Source: Nature, 2014 Aug 7;512(7512):78-81. doi: 10.1038/nature13383. Epub 2014 Jun 22.
Read More: Nature

Updates

A 2015 reviewby Marco Cosentino, Franca Marino and Georges Maestroni highlight the importance of the dysregulation of adrenergic fibers to the bone marrow (BM), which is associated with hematopoietic disturbances and myeloproliferative disease.

Sympathetic neuropathy has been recently proposed also as a novel mechanism for malignancies like acute myelogenous leukemia (AML) to exploit the hematopoietic microenvironment for its purposes.

Indeed, in an animal model of AML, a sympathetic neuropathy promotes leukemic BM infiltration, possibly through an expansion of perivascular mesenchymal stem and progenitor cells primed for osteoblastic differentiation at the expense of the physiological periarteriolar niche cells. Blockade of β₂-AR pathways enhanced AML infiltration whereas a β₂-AR agonist reduced disease activity.

These authors also discuss that the activation of sympathetic nervous system represents a link between chronic stress and up-regulation of proinflammatory responses, such as monocytosis and neutrophilia in humans not only provides a mechanistic explanation to the negative prognostic role of the neutrophil/lymphocyte ratio in a broad and heterogeneous number of critical conditions, such as cancer and cardiovascular disease but also offers several opportunities for therapeutic intervention.

Results obtained so far in preclinical models would already support to various extent the clinical evaluation of: the α₁-AR antagonist prazosin), β₂-AR agonists and dopaminergic agonists for HSC transplantation; α₁-AR agonists as well as dopaminergic agonists to protect against the adverse effects of cytotoxic agents on BM; β₂– and β₃-AR agonists in myeloproliferative disease.

A 2020 study indicates that patients with polycythemia vera, characterized by high hemoglobin concentrations and hematocrit levels had lower sympathetic nervous activity and decreased blood pressure variability as compared with controls.

Of note, all parameters of sympathetic nervous system activity assessed in this study – muscle sympathetic nerve activity (MSNA) and catecholamine levels, blood pressure variability and tendency toward slower heart rate, were lower in polycythemia vera than in controls.