Regulation of bone marrow hematopoietic stem cell is involved in high-altitude erythrocytosis.

ABSTRACT

OBJECTIVE: Hypoxia at high altitudes can lead to increased production of red blood cells through the hormone erythropoietin (EPO). In this study, we observed how the EPO-unresponsive hematopoietic stem cell (HSC) compartment responds to high-altitude hypoxic environments and contributes to erythropoiesis. MATERIALS AND METHODS: Using a mouse model at simulated high altitude, the bone marrow (BM) and spleen lineage marker(-)Sca-1(+)c-Kit(+) (LSK) HSC compartment were observed in detail. Normal LSK cells were then cultured under different conditions (varying EPO levels, oxygen concentrations, and BM supernatants) to investigate the causes of the HSC responses. RESULTS: Hypoxic mice exhibited a marked expansion in BM and spleen LSK compartments, which were associated with enhanced proliferation. BM HSCs seemed to play a more important role in erythropoiesis at high altitude than spleen HSCs. There was also a lineage fate change of BM HSCs in hypoxic mice that was manifested in increased megakaryocyte-erythrocyte progenitors and periodically reduced granulocyte-macrophage progenitors in the BM. The LSK cells in hypoxic mice displayed upregulated erythroid-specific GATA-1 and downregulated granulocyte-macrophage-specific PU.1 messenger RNA expression, as well as the capacity to differentiate into more erythroid precursors after culture. BM culture supernatant from hypoxic mice (but not elevated EPO or varying O(2) tension) could induce expansion and erythroid-priority differentiation of the HSC population, a phenomenon partially caused by increasing interleukin-3 and interleukin-6 secretion in the BM. CONCLUSIONS: The present study suggests a new EPO-independent HSC mechanism of high-altitude erythrocytosis.