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

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-CampeloDavid Valcarcel, Mikel Hernaez, Juan P Romero, Felipe Prosper

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.
Original languageEnglish (US)
JournaleLife
Volume12
DOIs
StatePublished - Jan 11 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-02-10

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Medicine
  • General Immunology and Microbiology
  • General Neuroscience

Fingerprint

Dive into the research topics of 'Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution.'. Together they form a unique fingerprint.

Cite this