Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single cell resolution
- Universidad de Navarra, Spain
- Clinica Universidad de Navarra, Spain
- Hospital Universitario de Salamanca, Spain
- Vall d'Hebron Hospital Universitari, Spain
- NavarraBiomed, Spain
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 (scRNAseq) to characterize an enriched population of human hematopoietic stem and progenitor cells (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 age-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks 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 gene regulatory networks (GRN) 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 TF 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.
Data availability
All the single cell RNA sequencing data is available at Gene Expression Omnibus under accession number GSE180298. The scripts needed to replicate the analysis are deposited on GitHub:https://github.com/mainciburu/scRNA-Hematopoiesis
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Single-cell, multi-omic analysis identifies regulatory programs in mixed phenotype acute leukemiaNCBI Gene Expression Omnibus, GSE139369.
Article and author information
Author details
Tamara Jiménez Solas
Funding
Instituto de Salud Carlos III
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Ministerio de Ciencia e Innovación (PhD fellowship FPU18/05488)
- Marina Ainciburu
Fundación Científica Asociación Española Contra el Cáncer (Investigador AECC award)
- Teresa Ezponda
H2020 Marie Skłodowska-Curie Actions (Grant Agreement No. 898356)
- Mikel Hernaez
Federación Española de Enfermedades Raras (PI17/00701,PI19/00726 and PI20/01308)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Centro de Investigación Biomédica en Red de Cáncer (CB16/12/00489 and CB16/12/00225)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Gobierno de Navarra (ERAPerMed MEET-AML 0011-2750-2019-000001; AGATA 0011-1411-2020-000010/0011-1411-2020-000011 and DIAN)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
la Caixa" Foundation " (GR-NET NORMAL-HIT HR20-00871)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Cancer Research UK (C355/A26819)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Fundación Científica Asociación Española Contra el Cáncer (Accelerator Award Program)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Associazione Italiana per la Ricerca sul Cancro (Accelerator Award Program)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de 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 Pablo Romero
- Felipe Prosper
Gobierno de Navarra (PhD fellowship 0011-0537-2019-000001)
- Nerea Berastegui
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jiwon Shim, Hanyang University, Republic of Korea
Ethics
Human subjects: The samples and data from the patients included in the study were provided by the Biobank of the University of Navarra and were processed according to standard operating procedures. Patients and healthy donors provided informed consent, together with consent for publication. The study was approved by the Clinical Research Ethics Committee of the Clinica Universidad de Navarra, following protocol # 2017.218.
Version history
- Preprint posted: July 31, 2021 (view preprint)
- Received: April 8, 2022
- Accepted: January 10, 2023
- Accepted Manuscript published: January 11, 2023 (version 1)
- Version of Record published: February 7, 2023 (version 2)
Copyright
© 2023, Ainciburu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single cell resolution
eLife 12:e79363.
https://doi.org/10.7554/eLife.79363
Further reading
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Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.
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