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Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development

Small numbers of hematopoietic stem cells (HSCs) balance self-renewal and differentiation to produce the diversity and abundance of cell types that make up the blood system. How nutrients are recruited to support this massive differentiation and proliferation process remains largely unknown. The uni...

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Autores principales: Abramowitz, Lara K., Harly, Christelle, Das, Arundhoti, Bhandoola, Avinash, Hanover, John A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715813/
https://www.ncbi.nlm.nih.gov/pubmed/31467334
http://dx.doi.org/10.1038/s41598-019-48991-8
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author Abramowitz, Lara K.
Harly, Christelle
Das, Arundhoti
Bhandoola, Avinash
Hanover, John A.
author_facet Abramowitz, Lara K.
Harly, Christelle
Das, Arundhoti
Bhandoola, Avinash
Hanover, John A.
author_sort Abramowitz, Lara K.
collection PubMed
description Small numbers of hematopoietic stem cells (HSCs) balance self-renewal and differentiation to produce the diversity and abundance of cell types that make up the blood system. How nutrients are recruited to support this massive differentiation and proliferation process remains largely unknown. The unique metabolism of adult HSCs, which rely on glycolysis and glutaminolysis, suggests a potential role for the post-translational modification O-GlcNAc as a critical nutrient signal in these cells. Glutamine, glucose, and other metabolites drive the hexosamine biosynthetic pathway (HBP) ultimately leading to the O-GlcNAc modification of critical intracellular targets. Here, we used a conditional targeted genetic deletion of the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), to determine the consequences of blocked O-GlcNAc cycling on HSCs. Oga deletion in mouse HSCs resulted in greatly diminished progenitor pools, impaired stem cell self-renewal and nearly complete loss of competitive repopulation capacity. Further, early T cell specification was particularly sensitive to Oga deletion. Loss of Oga resulted in a doubling of apoptotic cells within the bone marrow and transcriptional deregulation of key genes involved in adult stem cell maintenance and lineage specification. These findings suggest that O-GlcNAc cycling plays a critical role in supporting HSC homeostasis and early thymocyte development.
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spelling pubmed-67158132019-09-13 Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development Abramowitz, Lara K. Harly, Christelle Das, Arundhoti Bhandoola, Avinash Hanover, John A. Sci Rep Article Small numbers of hematopoietic stem cells (HSCs) balance self-renewal and differentiation to produce the diversity and abundance of cell types that make up the blood system. How nutrients are recruited to support this massive differentiation and proliferation process remains largely unknown. The unique metabolism of adult HSCs, which rely on glycolysis and glutaminolysis, suggests a potential role for the post-translational modification O-GlcNAc as a critical nutrient signal in these cells. Glutamine, glucose, and other metabolites drive the hexosamine biosynthetic pathway (HBP) ultimately leading to the O-GlcNAc modification of critical intracellular targets. Here, we used a conditional targeted genetic deletion of the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), to determine the consequences of blocked O-GlcNAc cycling on HSCs. Oga deletion in mouse HSCs resulted in greatly diminished progenitor pools, impaired stem cell self-renewal and nearly complete loss of competitive repopulation capacity. Further, early T cell specification was particularly sensitive to Oga deletion. Loss of Oga resulted in a doubling of apoptotic cells within the bone marrow and transcriptional deregulation of key genes involved in adult stem cell maintenance and lineage specification. These findings suggest that O-GlcNAc cycling plays a critical role in supporting HSC homeostasis and early thymocyte development. Nature Publishing Group UK 2019-08-29 /pmc/articles/PMC6715813/ /pubmed/31467334 http://dx.doi.org/10.1038/s41598-019-48991-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Abramowitz, Lara K.
Harly, Christelle
Das, Arundhoti
Bhandoola, Avinash
Hanover, John A.
Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
title Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
title_full Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
title_fullStr Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
title_full_unstemmed Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
title_short Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
title_sort blocked o-glcnac cycling disrupts mouse hematopoeitic stem cell maintenance and early t cell development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715813/
https://www.ncbi.nlm.nih.gov/pubmed/31467334
http://dx.doi.org/10.1038/s41598-019-48991-8
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