Abstract
Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
Highlights
We have previously shown that decreased plasma concentration of the soluble EPO receptor, an endogenous EPO antagonist, is among the factors that might explain Excessive erythrocytosis (EE) despite altitude-normal serum EPO in chronic mountain sickness (CMS) highlanders, because increased blood EPO availability to bind membrane EPOR would result in a stronger erythropoietic stimulus [50, 51]
When cultured under hypoxic conditions (1% O2), CMS-derived burst-forming unit-erythroid (BFU-E) colonies showed a greater proliferation rate compared with non-CMS colonies (367.3 Ϯ 89.1 vs. 100.9 Ϯ 19.1%, P Ͻ 0.01; Fig. 1B)
Total colony size was larger in CMS cells cultured in hypoxia compared with nonCMS cells (6.4 Ϯ 0.5 vs. 4.2 Ϯ 0.5 mm2, P Ͻ 0.01), and larger than CMS-derived colonies cultured in normoxia (6.4 Ϯ 0.5 vs. 3.2 Ϯ 0.8 mm2, P Ͻ 0.01; Fig. 1C)
Summary
We have previously shown that decreased plasma concentration of the soluble EPO receptor (sEPOR), an endogenous EPO antagonist, is among the factors that might explain EE despite altitude-normal serum EPO in CMS highlanders, because increased blood EPO availability to bind membrane EPOR would result in a stronger erythropoietic stimulus [50, 51]. Another suggested mechanism includes increased local expression of EPO in the bone marrow, associated with increased hypoxia inducible factor ␣ levels [48]. Erythroid progenitor cells of CMS individuals could, hypothetically, be more sensitive to EPO, and their proliferative response to hypoxia would be stronger than in non-CMS cells
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