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Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution
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-cel...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9904760/ https://www.ncbi.nlm.nih.gov/pubmed/36629404 http://dx.doi.org/10.7554/eLife.79363 |
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author | Ainciburu, Marina Ezponda, Teresa Berastegui, Nerea Alfonso-Pierola, Ana Vilas-Zornoza, Amaia San Martin-Uriz, Patxi Alignani, Diego Lamo-Espinosa, Jose San-Julian, Mikel Jiménez-Solas, Tamara Lopez, Felix Muntion, Sandra Sanchez-Guijo, Fermin Molero, Antonieta Montoro, Julia Serrano, Guillermo Diaz-Mazkiaran, Aintzane Lasaga, Miren Gomez-Cabrero, David Diez-Campelo, Maria Valcarcel, David Hernaez, Mikel Romero, Juan P Prosper, Felipe |
author_facet | Ainciburu, Marina Ezponda, Teresa Berastegui, Nerea Alfonso-Pierola, Ana Vilas-Zornoza, Amaia San Martin-Uriz, Patxi Alignani, Diego Lamo-Espinosa, Jose San-Julian, Mikel Jiménez-Solas, Tamara Lopez, Felix Muntion, Sandra Sanchez-Guijo, Fermin Molero, Antonieta Montoro, Julia Serrano, Guillermo Diaz-Mazkiaran, Aintzane Lasaga, Miren Gomez-Cabrero, David Diez-Campelo, Maria Valcarcel, David Hernaez, Mikel Romero, Juan P Prosper, Felipe |
author_sort | Ainciburu, Marina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9904760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-99047602023-02-08 Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution Ainciburu, Marina Ezponda, Teresa Berastegui, Nerea Alfonso-Pierola, Ana Vilas-Zornoza, Amaia San Martin-Uriz, Patxi Alignani, Diego Lamo-Espinosa, Jose San-Julian, Mikel Jiménez-Solas, Tamara Lopez, Felix Muntion, Sandra Sanchez-Guijo, Fermin Molero, Antonieta Montoro, Julia Serrano, Guillermo Diaz-Mazkiaran, Aintzane Lasaga, Miren Gomez-Cabrero, David Diez-Campelo, Maria Valcarcel, David Hernaez, Mikel Romero, Juan P Prosper, Felipe eLife Computational and Systems Biology 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. eLife Sciences Publications, Ltd 2023-01-11 /pmc/articles/PMC9904760/ /pubmed/36629404 http://dx.doi.org/10.7554/eLife.79363 Text en © 2023, Ainciburu, Ezponda et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Computational and Systems Biology Ainciburu, Marina Ezponda, Teresa Berastegui, Nerea Alfonso-Pierola, Ana Vilas-Zornoza, Amaia San Martin-Uriz, Patxi Alignani, Diego Lamo-Espinosa, Jose San-Julian, Mikel Jiménez-Solas, Tamara Lopez, Felix Muntion, Sandra Sanchez-Guijo, Fermin Molero, Antonieta Montoro, Julia Serrano, Guillermo Diaz-Mazkiaran, Aintzane Lasaga, Miren Gomez-Cabrero, David Diez-Campelo, Maria Valcarcel, David Hernaez, Mikel Romero, Juan P Prosper, Felipe Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
title | Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
title_full | Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
title_fullStr | Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
title_full_unstemmed | Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
title_short | Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
title_sort | uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution |
topic | Computational and Systems Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9904760/ https://www.ncbi.nlm.nih.gov/pubmed/36629404 http://dx.doi.org/10.7554/eLife.79363 |
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