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


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.
Department of High Altitude Military Hygiene, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, PR China.
Peng
P
Li
Jian
J
Huang
Huai-jun
HJ
Tian
Qing-yuan
QY
Huang
Chun-hua
CH
Jiang
Yu-qi
YQ
Gao
D000531:Altitude; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000378:metabolism; D011086:Polycythemia / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D017931:DNA Primers; D004921:Erythropoietin; D010100:Oxygen