Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with chronic mountain sickness

• DOI: 10.1152/ajpregu.00250.2019
• Publication Date: 2019-10-16T09:36:39Z
• Authors: Daniela Bermudez; Priti Azad; Rómulo Figueroa-M...; Gustavo Vizcardo-...; Noemí Corante; Cristina Guerra-G...; Gabriel G. Haddad; Francisco C. Vill...
• Keywords: 0301 basic medicine; https://purl.org/pe-repo/ocde/ford#3.01.08; Cancer Research; Physiology; Gene Expression Regulation/drug effects; Brown Adipose Tissue Function and Physiology; Altitude Sickness; Genetic and Physiological Adaptations to High-Altitude Environments; Endocrinology; Homeostasis; Erythropoiesis; Hypoxia; excessive erythrocytosis; Internal medicine; chronic mountain sickness; Erythroid Precursor Cells; Stem cell; Altitude; Life Sciences; Anemia; Erythropoietin/blood; Progenitor cell; Medicine; Research Article; Cell biology; Acute Mountain Sickness; Erythroid Precursor Cells/metabolism; Iron; Immunology; Cancer research; 03 medical and health sciences; GATA1; Biochemistry, Genetics and Molecular Biology; high altitude; Health Sciences; Genetics; Humans; Genetic Predisposition to Disease; Oxygen/metabolism/pharmacology; Erythropoietin; Biology; Altitude Sickness/epidemiology; FOS: Clinical medicine; Oxygen; Haematopoiesis; Gene Expression Regulation; FOS: Biological sciences; Chronic Disease; Leukocytes, Mononuclear; Metabolic Reprogramming in Cancer Biology; Andean; Transcriptome; Iron/metabolism; erythropoiesis

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.