TY  - JOUR
AU  - Poisa-Beiro, Laura
AU  - Landry, Jonathan J M
AU  - Yan, Bowen
AU  - Kardorff, Michael
AU  - Eckstein, Volker
AU  - Villacorta, Laura
AU  - Krammer, Peter
AU  - Zaugg, Judith
AU  - Gavin, Anne-Claude
AU  - Benes, Vladimir
AU  - Zhou, Daohong
AU  - Raffel, Simon
AU  - Ho, Anthony D
TI  - A Senescent Cluster in Aged Human Hematopoietic Stem Cell Compartment as Target for Senotherapy.
JO  - International journal of molecular sciences
VL  - 26
IS  - 2
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2025-00233
SP  - 787
PY  - 2025
AB  - 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.
KW  - Hematopoietic Stem Cells: metabolism
KW  - Hematopoietic Stem Cells: cytology
KW  - Humans
KW  - Cellular Senescence
KW  - Animals
KW  - Mice
KW  - Aging
KW  - Senotherapeutics: pharmacology
KW  - Hematopoiesis
KW  - Transcriptome
KW  - Aged
KW  - Adult
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Tumor Suppressor Protein p53: genetics
KW  - DNA Damage
KW  - Male
KW  - Gene Expression Profiling
KW  - aging (Other)
KW  - comparative single-cell transcriptomics (Other)
KW  - hematopoietic stem and progenitor cells (HSPC) (Other)
KW  - senescence signature (Other)
KW  - Senotherapeutics (NLM Chemicals)
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39859500
C2  - pmc:PMC11766015
DO  - DOI:10.3390/ijms26020787
UR  - https://inrepo02.dkfz.de/record/298226
ER  -