Circulating hematopoietic stem/progenitor cell subsets contribute to human hematopoietic homeostasis

Published: 21 March 2024| Version 1 | DOI: 10.17632/jywsy5zz96.1
, Pamela Quaranta


In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPC) are present in the peripheral blood but their contribution to hematopoietic homeostasis in humans remain unsolved. By integrating advanced immunophenotyping, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), functional single-cell assays and integration site (IS) clonal tracking, we unveiled the phenotypic composition, the transcriptional features and the biological role of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPC progressively reduced in cell count over aging and are enriched for primitive, lymphoid and erythroid subpopulations, showing pre-activated transcriptional and functional state. Moreover, cHSPC have low expression of multiple BM-retention molecules, but maintain their homing potential after xenotransplantation. By generating a comprehensive Human Organ-Resident HSPC (HuOR) dataset based on scRNAseq data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Of note, circulating multi-lymphoid progenitors (MLP) are primed for seeding the thymus and actively contribute to T-cell production at steady state in patients treated with HSPC-gene therapy (GT). Human clonal tracking data from GT patients also showed that cHSPC connect distant BM niches and participate to steady-state hematopoietic production, with primitive cHSPC having the highest re-circulation capability to travel in and out the BM. Finally, in case of hematopoietic impairment, cHSPC composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis.


Steps to reproduce

Please refer to


San Raffaele Telethon Institute for Gene Therapy, Ospedale San Raffaele, Universita Vita Salute San Raffaele, Weill Cornell Medicine Department of Pathology and Laboratory Medicine, Universita degli Studi di Milano, Ospedale Maggiore Policlinico


Gene Therapy, Hematopoietic Stem Cell, General Hematopoiesis, Single-Cell Transcriptomics


Fondazione Telethon

TIGET Core Grant B2

Fondazione Telethon


Ministero della Salute


European Commission


Else Kröner-Fresenius-Stiftung

Prize to Alessandro Aiuti