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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- Computational and Systems Biology
- Medicine
Background:
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.
Methods:
Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations.
Results:
Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB.
Conclusions:
The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes.
Funding:
This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.
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- Computational and Systems Biology
- Genetics and Genomics
Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (P-value=1.82×10-11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.
