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The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments

Age‐related thymus involution results in decreased T‐cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circ...

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Autores principales: Srinivasan, Jayashree, Vasudev, Anusha, Shasha, Carolyn, Selden, Hilary J., Perez, Encarnacion, LaFleur, Bonnie, Sinari, Shripad A., Krueger, Andreas, Richie, Ellen R., Ehrlich, Lauren I. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410006/
https://www.ncbi.nlm.nih.gov/pubmed/37221658
http://dx.doi.org/10.1111/acel.13870
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author Srinivasan, Jayashree
Vasudev, Anusha
Shasha, Carolyn
Selden, Hilary J.
Perez, Encarnacion
LaFleur, Bonnie
Sinari, Shripad A.
Krueger, Andreas
Richie, Ellen R.
Ehrlich, Lauren I. R.
author_facet Srinivasan, Jayashree
Vasudev, Anusha
Shasha, Carolyn
Selden, Hilary J.
Perez, Encarnacion
LaFleur, Bonnie
Sinari, Shripad A.
Krueger, Andreas
Richie, Ellen R.
Ehrlich, Lauren I. R.
author_sort Srinivasan, Jayashree
collection PubMed
description Age‐related thymus involution results in decreased T‐cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)‐derived thymus seeding progenitors (TSPs) that differentiate into early T‐cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre‐thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre‐thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age‐associated thymus involution.
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spelling pubmed-104100062023-08-10 The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments Srinivasan, Jayashree Vasudev, Anusha Shasha, Carolyn Selden, Hilary J. Perez, Encarnacion LaFleur, Bonnie Sinari, Shripad A. Krueger, Andreas Richie, Ellen R. Ehrlich, Lauren I. R. Aging Cell Research Articles Age‐related thymus involution results in decreased T‐cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)‐derived thymus seeding progenitors (TSPs) that differentiate into early T‐cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre‐thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre‐thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age‐associated thymus involution. John Wiley and Sons Inc. 2023-05-23 /pmc/articles/PMC10410006/ /pubmed/37221658 http://dx.doi.org/10.1111/acel.13870 Text en © 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Srinivasan, Jayashree
Vasudev, Anusha
Shasha, Carolyn
Selden, Hilary J.
Perez, Encarnacion
LaFleur, Bonnie
Sinari, Shripad A.
Krueger, Andreas
Richie, Ellen R.
Ehrlich, Lauren I. R.
The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
title The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
title_full The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
title_fullStr The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
title_full_unstemmed The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
title_short The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
title_sort initial age‐associated decline in early t‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410006/
https://www.ncbi.nlm.nih.gov/pubmed/37221658
http://dx.doi.org/10.1111/acel.13870
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