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An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads

The Bajau Sea Nomads were recently demonstrated to have evolved larger spleens as an adaptation to millennia of a marine foraging lifestyle. The large-spleen phenotype appears to derive from increases in thyroid hormone (TH) production as a result of reduced expression of phosphodiesterase 10A (PDE1...

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Autores principales: Ilardo, Melissa, dos Santos, Maria C. Ferreira, Grote Beverborg, Niels, Rajan, Malini, Said, M. Abdullah, Verweij, Niek, Van Der Harst, Pim, Van Der Meer, Peter, Leibold, Elizabeth A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846933/
https://www.ncbi.nlm.nih.gov/pubmed/35177992
http://dx.doi.org/10.3389/fphys.2021.760851
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author Ilardo, Melissa
dos Santos, Maria C. Ferreira
Grote Beverborg, Niels
Rajan, Malini
Said, M. Abdullah
Verweij, Niek
Van Der Harst, Pim
Van Der Meer, Peter
Leibold, Elizabeth A.
author_facet Ilardo, Melissa
dos Santos, Maria C. Ferreira
Grote Beverborg, Niels
Rajan, Malini
Said, M. Abdullah
Verweij, Niek
Van Der Harst, Pim
Van Der Meer, Peter
Leibold, Elizabeth A.
author_sort Ilardo, Melissa
collection PubMed
description The Bajau Sea Nomads were recently demonstrated to have evolved larger spleens as an adaptation to millennia of a marine foraging lifestyle. The large-spleen phenotype appears to derive from increases in thyroid hormone (TH) production as a result of reduced expression of phosphodiesterase 10A (PDE10A), though the exact mechanism remains unknown. Through pharmacological inhibition of PDE10A using the selective inhibitor MP-10 in mice, we were able to mimic the Bajau adaptation and show that treated mice had significantly larger spleens than control animals. This difference appears connected to an excess of early stage erythrocytes and an apparent increase in red blood cell (RBC) precursor proliferation in response to increased TH. However, we determined that the stimulation of RBC production in the mouse model via TH is Erythropoietin (EPO)-independent, unlike in the altitude (chronic hypoxemia) response. We confirmed this using human GWAS data; although the Bajau PDE10A variants are significantly associated with increased TH levels and RBC count, they are not associated with EPO levels, nor are other strongly thyroid-associated SNPs. We therefore suggest that an EPO-independent mechanism of stimulating RBC precursor proliferation via TH upregulation underlies the increase in spleen size observed in Sea Nomad populations.
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spelling pubmed-88469332022-02-16 An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads Ilardo, Melissa dos Santos, Maria C. Ferreira Grote Beverborg, Niels Rajan, Malini Said, M. Abdullah Verweij, Niek Van Der Harst, Pim Van Der Meer, Peter Leibold, Elizabeth A. Front Physiol Physiology The Bajau Sea Nomads were recently demonstrated to have evolved larger spleens as an adaptation to millennia of a marine foraging lifestyle. The large-spleen phenotype appears to derive from increases in thyroid hormone (TH) production as a result of reduced expression of phosphodiesterase 10A (PDE10A), though the exact mechanism remains unknown. Through pharmacological inhibition of PDE10A using the selective inhibitor MP-10 in mice, we were able to mimic the Bajau adaptation and show that treated mice had significantly larger spleens than control animals. This difference appears connected to an excess of early stage erythrocytes and an apparent increase in red blood cell (RBC) precursor proliferation in response to increased TH. However, we determined that the stimulation of RBC production in the mouse model via TH is Erythropoietin (EPO)-independent, unlike in the altitude (chronic hypoxemia) response. We confirmed this using human GWAS data; although the Bajau PDE10A variants are significantly associated with increased TH levels and RBC count, they are not associated with EPO levels, nor are other strongly thyroid-associated SNPs. We therefore suggest that an EPO-independent mechanism of stimulating RBC precursor proliferation via TH upregulation underlies the increase in spleen size observed in Sea Nomad populations. Frontiers Media S.A. 2022-01-27 /pmc/articles/PMC8846933/ /pubmed/35177992 http://dx.doi.org/10.3389/fphys.2021.760851 Text en Copyright © 2022 Ilardo, dos Santos, Grote Beverborg, Rajan, Said, Verweij, Van Der Harst, Van Der Meer and Leibold. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Ilardo, Melissa
dos Santos, Maria C. Ferreira
Grote Beverborg, Niels
Rajan, Malini
Said, M. Abdullah
Verweij, Niek
Van Der Harst, Pim
Van Der Meer, Peter
Leibold, Elizabeth A.
An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
title An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
title_full An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
title_fullStr An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
title_full_unstemmed An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
title_short An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
title_sort erythropoietin-independent mechanism of erythrocytic precursor proliferation underlies hypoxia tolerance in sea nomads
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846933/
https://www.ncbi.nlm.nih.gov/pubmed/35177992
http://dx.doi.org/10.3389/fphys.2021.760851
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