Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with Chronic Mountain Sickness.

Vizcardo-Galindo, Gustavo; Haddad, Gabriel G.; Figueroa-Mujica, Romulo; Corante, Noemi; Bermudez, Daniela; Azad, Priti; Guerra-Giraldez, Cristina; Villafuerte, Francisco C.

dc.contributor.author	Bermudez, Daniela
dc.contributor.author	Azad, Priti
dc.contributor.author	Figueroa-Mujica, Romulo
dc.contributor.author	Vizcardo-Galindo, Gustavo
dc.contributor.author	Corante, Noemi
dc.contributor.author	Guerra-Giraldez, Cristina
dc.contributor.author	Haddad, Gabriel G.
dc.contributor.author	Villafuerte, Francisco C.
dc.date.accessioned	2019-12-06T20:57:40Z
dc.date.available	2019-12-06T20:57:40Z
dc.date.issued	2019
dc.identifier.uri	https://hdl.handle.net/20.500.12866/7360
dc.description.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 BFU-E cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their SENP1, GATA1, EPOR, and EPO 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 to non-CMS cells, together with an up-regulated 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.	en_US
dc.language.iso	eng
dc.publisher	American Physiological Society
dc.relation.ispartofseries	American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	Humans	en_US
dc.subject	Chronic Disease	en_US
dc.subject	Genetic Predisposition to Disease	en_US
dc.subject	Altitude	en_US
dc.subject	Andean	en_US
dc.subject	chronic mountain sickness	en_US
dc.subject	erythropoiesis	en_US
dc.subject	excessive erythrocytosis	en_US
dc.subject	high altitude	en_US
dc.subject	Altitude Sickness/epidemiology	en_US
dc.subject	Erythroid Precursor Cells/metabolism	en_US
dc.subject	Erythropoietin/blood	en_US
dc.subject	Gene Expression Regulation/drug effects	en_US
dc.subject	Homeostasis	en_US
dc.subject	Hypoxia	en_US
dc.subject	Iron/metabolism	en_US
dc.subject	Leukocytes, Mononuclear	en_US
dc.subject	Oxygen/metabolism/pharmacology	en_US
dc.subject	Transcriptome	en_US
dc.title	Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with Chronic Mountain Sickness.	en_US
dc.type	info:eu-repo/semantics/article
dc.identifier.doi	https://doi.org/10.1152/ajpregu.00250.2019
dc.subject.ocde	https://purl.org/pe-repo/ocde/ford#3.01.08
dc.relation.issn	1522-1490