Back to Search Start Over

Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution

Authors :
Marina Ainciburu
Teresa Ezponda
Nerea Berastegui
Ana Alfonso-Pierola
Amaia Vilas-Zornoza
Patxi San Martin-Uriz
Diego Alignani
Jose Lamo-Espinosa
Mikel San-Julian
Tamara Jiménez-Solas
Felix Lopez
Sandra Muntion
Fermin Sanchez-Guijo
Antonieta Molero
Julia Montoro
Guillermo Serrano
Aintzane Diaz-Mazkiaran
Miren Lasaga
David Gomez-Cabrero
Maria Diez-Campelo
David Valcarcel
Mikel Hernaez
Juan P Romero
Felipe Prosper
Source :
eLife, Vol 12 (2023)
Publication Year :
2023
Publisher :
eLife Sciences Publications Ltd, 2023.

Abstract

Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease. In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients.

Details

Language :
English
ISSN :
2050084X
Volume :
12
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.3e9c063b4a474f658aaf2538b69955f6
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.79363