Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging
Hematopoietic stem/progenitor cells (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. HSPCs from older individuals exhibited repopulating frequencies comparable with those from younger donors in both primary and secondary xenografts; however, aged HSCs displayed impaired differentiation, chromatin and cell cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features after 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.
Authors
- Edoardo Carsana
- Rosa Di Micco (ORCID: https://orcid.org/0000-0002-2575-8729)
- Kerstin B. Kaufmann (ORCID: https://orcid.org/0000-0001-5013-6123)
- Pamela Quaranta (ORCID: https://orcid.org/0009-0009-2988-5387)
- Teresa Tavella
- Ivan Merelli (ORCID: https://orcid.org/0000-0003-3587-3680)
- Kety Giannetti (ORCID: https://orcid.org/0000-0001-7989-2520)
- Luca Basso‐Ricci (ORCID: https://orcid.org/0000-0002-5907-005X)
- Raisa Jofra Hernández (ORCID: https://orcid.org/0000-0002-9812-9042)
- Marco Ometti (ORCID: https://orcid.org/0000-0002-9868-2745)
- Emanuele Lettera
- Stephanie Zhi-Juan Xie (ORCID: https://orcid.org/0000-0002-0284-494X)
- Alicia G. Aguilar-Navarro (ORCID: https://orcid.org/0000-0001-6409-0613)
- Lucrezia della Volpe (ORCID: https://orcid.org/0000-0002-9087-1293)
- S. Beretta
- Guido Pacini (ORCID: https://orcid.org/0000-0001-6506-6949)
- Elena Lo Furno
- Luca Seffin (ORCID: https://orcid.org/0009-0005-7028-6125)
- Andrea Conti
- Giacomo Farina
- Alessandro Aiuti
- Nicolò Gualandi
- Alex Murison
- Eugenia Flores-Figueroa
- Serena Scala
- Laura Garcia-Prat
Institutions
- Vita-Salute San Raffaele University (IT)
- University of Toronto (CA)
- Istituto Universitario di Studi Superiori di Pavia (IT)
- Princess Margaret Cancer Centre (CA)
- Centro Medico Nacional Siglo XXI (MX)
- IRCCS Ospedale San Raffaele (IT)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1084/jem.20251805
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 0.00