Molecular and Phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging
Description
Hematopoietic stem/progenitor cell (HSPC) aging has long been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across the human lifespan has been lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis from youth to advanced age. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity declined, especially for erythroid and lymphoid lineages. HSPC from older individuals exhibited repopulating frequencies comparable to those from younger donors in both primary and secondary xenografts; however, aged HSC displayed impaired differentiation, chromatin and cell-cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features post-xenotransplantation. Importantly, imposing proliferative stress on young human HSPCs in vivo recapitulated key aging-associated phenotypic and functional declines. Together, our findings identify dysregulated activation responses as a defining feature of HSPC aging and establish proliferative stress–based xenotransplantation models as powerful platforms for investigating age-related hematopoietic dysfunctions. This work is published on Journal of Experimental Medicine (doi: 10.1084/jem.20251805) All the data generated in this study have been deposited in the San Raffaele Open Research Data Repository under accession code doi: 10.17632/72ty5v9djn.1 The RNA and ATAC sequencing data generated and discussed in this study have been deposited in NCBI's Gene Expression Omnibus (Edgar et al., 2002) and are accessible through GEO SuperSeries GSE311225, which contains the following data: GSE243327 (RNA-seq), GSE311221 (ATAC-seq). The code used to process and to generate the images of RNAseq data in this manuscript is available at: http://www.bioinfotiget.it/gitlab/custom/LetteraScala_Ageing/bulk_RNAseq. WES data generated and discussed in this study are available at the European Nucleotide Archive (ENA) under the following accession code: PRJEB93902
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Please refer to: doi: 10.1084/jem.20251805)
Institutions
- IRCCS Ospedale San RaffaeleLombardy, Milan
- Universita Vita Salute San RaffaeleLombardia, Milano
- Princess Margaret Hospital Cancer CentreON, Toronto
- Instituto Mexicano del Seguro SocialDF, Mexico
- Scuola Universitaria Superiore PaviaPavia
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Funders
- International Human Frontier Science Program OrganizationGrand Est, FranceGrant ID: Career Development Award
- New York Academy of SciencesNew York, United StatesGrant ID: Interstellar Initiative on Healthy Longevity
- American Society of HematologyDistrict of Columbia, United StatesGrant ID: ASH Global Research Award
- New York Stem Cell FoundationNew York, United States
- European Research CouncilEuropean CommissionBrussels Capital, BelgiumGrant ID: Consolidator grant 101003186, ReviveSTEM
- European CommissionEuropean UnionBrussels Capital, BelgiumGrant ID: X-PAND Pathfinder European Commission grant (G.A. 101070950)