Noncellular Niche Influences: Nervous System Mediators, Metabolic Mediators, and Hypoxia/Oxidative Stress

Hematopoietic stem cells (HSCs) traffic between bone marrow and circulation, what allows for life-saving clinical transplantation. Our previous work has shown that HSC numbers in blood follow circadian oscillations that are regulated by the central pacemaker in the brain, which reaches bone marrow nestin⁺ mesenchymal stem cells through peripheral sympathetic nerves. In the perinatal bone marrow, HSC-niche forming mesenchymal stem cells might be different from those that form the skeleton and some of them might be neural crest-derived, like peripheral neurons and supporting glial cells. Thus, tight regulation of the bone marrow stem-cell niche in vertebrates might build upon developmental relationships of its cellular components. We have found recently that cholinergic nerves regulate HSC maintenance, proliferation and migration in divergent niches. We will present unpublished evidence of how both branches of the autonomic nervous system cooperate to regulate HSC maintenance and function in spatially and temporally distinct niches. Moreover, we have shown recently that damage to this regulatory network is essential for the manifestation of myeloproliferative neoplasms. In these diseases, previously thought to be driven solely by mutated HSCs, protecting the HSC niche might represent a novel therapeutic strategy. Patients with myeloproliferative neoplasms have a higher risk of developing acute leukemia. However, at this stage, leukemic cells might be less sensitive to the normal control by the microenvironment and, instead, acute myelogenous leukemic cells might transform the bone marrow niches to support their own survival. We will discuss potential contributions of HSC niches to myeloproliferative neoplasms and MLL-AF9-driven acute myeloid leukemia.