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Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with Chronic Mountain Sickness
- Source :
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publication Year :
- 2019
- Publisher :
- American Physiological Society, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Physiology
Iron
Erythroid Precursor Cells/metabolism
Gene Expression Regulation/drug effects
Altitude Sickness
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
Gene expression
high altitude
Medicine
Humans
Homeostasis
Genetic Predisposition to Disease
Erythroid Progenitor Cells
Hypoxia
Oxygen/metabolism/pharmacology
Clinical syndrome
Erythropoietin
excessive erythrocytosis
health care economics and organizations
Altitude Sickness/epidemiology
chronic mountain sickness
Erythroid Precursor Cells
business.industry
purl.org/pe-repo/ocde/ford#3.01.08 [https]
Altitude
Erythropoietin/blood
Effects of high altitude on humans
medicine.disease
Proliferative response
Oxygen
030104 developmental biology
Chronic mountain sickness
Gene Expression Regulation
Immunology
Chronic Disease
Leukocytes, Mononuclear
Erythropoiesis
Andean
business
Transcriptome
Iron/metabolism
030217 neurology & neurosurgery
erythropoiesis
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Accession number :
- edsair.doi.dedup.....4286be60c0f035a9dd55c684bda53dab