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Stem cell decoupling underlies impaired lymphoid development during aging

Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with pref...

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Autores principales: Jang, Geunhyo, Contreras Castillo, Stephania, Esteva, Eduardo, Upadhaya, Samik, Feng, Jue, Adams, Nicholas M., Richard, Elodie, Awatramani, Rajeshwar, Sawai, Catherine M., Reizis, Boris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236001/
https://www.ncbi.nlm.nih.gov/pubmed/37216517
http://dx.doi.org/10.1073/pnas.2302019120
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author Jang, Geunhyo
Contreras Castillo, Stephania
Esteva, Eduardo
Upadhaya, Samik
Feng, Jue
Adams, Nicholas M.
Richard, Elodie
Awatramani, Rajeshwar
Sawai, Catherine M.
Reizis, Boris
author_facet Jang, Geunhyo
Contreras Castillo, Stephania
Esteva, Eduardo
Upadhaya, Samik
Feng, Jue
Adams, Nicholas M.
Richard, Elodie
Awatramani, Rajeshwar
Sawai, Catherine M.
Reizis, Boris
author_sort Jang, Geunhyo
collection PubMed
description Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential (“myeloid bias”). Here, we tested this notion using inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid, and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker Aldh1a1 confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in older mice.
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spelling pubmed-102360012023-11-22 Stem cell decoupling underlies impaired lymphoid development during aging Jang, Geunhyo Contreras Castillo, Stephania Esteva, Eduardo Upadhaya, Samik Feng, Jue Adams, Nicholas M. Richard, Elodie Awatramani, Rajeshwar Sawai, Catherine M. Reizis, Boris Proc Natl Acad Sci U S A Biological Sciences Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential (“myeloid bias”). Here, we tested this notion using inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid, and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker Aldh1a1 confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in older mice. National Academy of Sciences 2023-05-22 2023-05-30 /pmc/articles/PMC10236001/ /pubmed/37216517 http://dx.doi.org/10.1073/pnas.2302019120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Jang, Geunhyo
Contreras Castillo, Stephania
Esteva, Eduardo
Upadhaya, Samik
Feng, Jue
Adams, Nicholas M.
Richard, Elodie
Awatramani, Rajeshwar
Sawai, Catherine M.
Reizis, Boris
Stem cell decoupling underlies impaired lymphoid development during aging
title Stem cell decoupling underlies impaired lymphoid development during aging
title_full Stem cell decoupling underlies impaired lymphoid development during aging
title_fullStr Stem cell decoupling underlies impaired lymphoid development during aging
title_full_unstemmed Stem cell decoupling underlies impaired lymphoid development during aging
title_short Stem cell decoupling underlies impaired lymphoid development during aging
title_sort stem cell decoupling underlies impaired lymphoid development during aging
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236001/
https://www.ncbi.nlm.nih.gov/pubmed/37216517
http://dx.doi.org/10.1073/pnas.2302019120
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