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

造血 干细胞 祖细胞 造血干细胞 生物 免疫学 造血细胞 造血干细胞移植 平衡 细胞生物学
作者
Pamela Quaranta,Luca Basso‐Ricci,Raisa Jofra Hernández,Guido Pacini,Matteo Maria Naldini,Matteo Barcella,Luca Seffin,Giulia Pais,Giulio Spinozzi,Fabrizio Benedicenti,Carlo Pietrasanta,Jin‐Gyu Cheong,Andrea Ronchi,Lorenza Pugni,Francesca Dionisio,Ilaria Monti,Stefania Giannelli,Silvia Darin,Federico Fraschetta,Graziano Barera
出处
期刊:Blood [Elsevier BV]
卷期号:143 (19): 1937-1952 被引量:6
标识
DOI:10.1182/blood.2023022666
摘要

Abstract In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPCs) are present in the peripheral blood, but their contribution to human hematopoiesis remain unsolved. By integrating advanced immunophenotyping, single-cell transcriptional and functional profiling, and integration site (IS) clonal tracking, we unveiled the biological properties and the transcriptional features of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPCs reduced in cell count over aging and are enriched for primitive, lymphoid, and erythroid subpopulations, showing preactivated transcriptional and functional state. Moreover, cHSPCs have low expression of multiple BM-retention molecules but maintain their homing potential after xenotransplantation. By generating a comprehensive human organ-resident HSPC data set based on single-cell RNA sequencing data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Notably, circulating multi-lymphoid progenitors are primed for seeding the thymus and actively contribute to T-cell production. Human clonal tracking data from patients receiving gene therapy (GT) also showed that cHSPCs connect distant BM niches and participate in steady-state hematopoietic production, with primitive cHSPCs having the highest recirculation capability to travel in and out of the BM. Finally, in case of hematopoietic impairment, cHSPCs 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. GT patients’ clinical trials were registered at ClinicalTrials.gov (NCT01515462 and NCT03837483) and EudraCT (2009-017346-32 and 2018-003842-18).
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