Journal Article

DKFZ-2025-00233

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Senescent Cluster in Aged Human Hematopoietic Stem Cell Compartment as Target for Senotherapy.

Poisa-Beiro, L. ; Landry, J. J. M. ; Yan, B. ; Kardorff, M. ; Eckstein, V. ; Villacorta, L. ; Krammer, P.DKFZ* ; Zaugg, J. ; Gavin, A.-C. ; Benes, V. ; Zhou, D. ; Raffel, S. ; Ho, A. D.

2025
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms26020787

Abstract: To identify the differences between aged and young human hematopoiesis, we performed a direct comparison of aged and young human hematopoietic stem and progenitor cells (HSPCs). Alterations in transcriptome profiles upon aging between humans and mice were then compared. Human specimens consist of CD34+ cells from bone marrow, and mouse specimens of hematopoietic stem cells (HSCs; Lin- Kit+ Sca1+ CD150+). Single-cell transcriptomic studies, functional clustering, and developmental trajectory analyses were performed. A significant increase in multipotent progenitor 2A (MPP2A) cluster is found in the early HSC trajectory in old human subjects. This cluster is enriched in senescence signatures (increased telomere attrition, DNA damage, activation of P53 pathway). In mouse models, the accumulation of an analogous subset was confirmed in the aged LT-HSC population. Elimination of this subset has been shown to rejuvenate hematopoiesis in mice. A significant activation of the P53-P21WAF1/CIP1 pathway was found in the MPP2A population in humans. In contrast, the senescent HSCs in mice are characterized by activation of the p16Ink4a pathway. Aging in the human HSC compartment is mainly caused by the clonal evolution and accumulation of a senescent cell cluster. A population with a similar senescence signature in the aged LT-HSCs was confirmed in the murine aging model. Clearance of this senescent population with senotherapy in humans is feasible and potentially beneficial.

Keyword(s): Hematopoietic Stem Cells: metabolism (MeSH) ; Hematopoietic Stem Cells: cytology (MeSH) ; Humans (MeSH) ; Cellular Senescence (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Aging (MeSH) ; Senotherapeutics: pharmacology (MeSH) ; Hematopoiesis (MeSH) ; Transcriptome (MeSH) ; Aged (MeSH) ; Adult (MeSH) ; Tumor Suppressor Protein p53: metabolism (MeSH) ; Tumor Suppressor Protein p53: genetics (MeSH) ; DNA Damage (MeSH) ; Male (MeSH) ; Gene Expression Profiling (MeSH) ; aging ; comparative single-cell transcriptomics ; hematopoietic stem and progenitor cells (HSPC) ; senescence signature ; Senotherapeutics ; Tumor Suppressor Protein p53

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Contributing Institute(s):

1. Immungenetik (D030)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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