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

被引：20

作者：

Ainciburu, Marina ^{[1
,2
]}

Ezponda, Teresa ^{[1
,2
]}

Berastegui, Nerea ^{[1
]}

Alfonso-Pierola, Ana ^{[2
,3
]}

Vilas-Zornoza, Amaia ^{[1
,2
]}

San Martin-Uriz, Patxi ^{[1
,2
]}

Alignani, Diego ^{[4
]}

Lamo-Espinosa, Jose ^{[3
]}

San-Julian, Mikel ^{[3
]}

Jimenez-Solas, Tamara ^{[5
]}

Lopez, Felix ^{[5
]}

Muntion, Sandra ^{[5
,6
]}

Sanchez-Guijo, Fermin ^{[5
,6
]}

Molero, Antonieta ^{[7
]}

Montoro, Julia ^{[7
]}

Serrano, Guillermo ^{[8
]}

Diaz-Mazkiaran, Aintzane ^{[2
,8
]}

Lasaga, Miren ^{[9
]}

Gomez-Cabrero, David ^{[9
,10
]}

Diez-Campelo, Maria ^{[5
]}

Valcarcel, David ^{[7
]}

Hernaez, Mikel ^{[8
]}

Romero, Juan P. ^{[1
,2
]}

Prosper, Felipe ^{[1
,2
,3
,6
]}

机构：

[1] Univ Navarra, Ctr Invest Med Aplicada, Area Hemato Oncol, Inst Invest Sanit Navarra IDISNA, Pamplona, Spain

[2] Ctr Invest Biomed Red Canc, Madrid, Spain

[3] Clin Univ Navarra, Pamplona, Spain

[4] Univ Navarra, Flow Cytometry Core, Pamplona, Spain

[5] Hosp Univ Salamanca, Salamanca, Spain

[6] ISCIII, Red Invest Cooperat Terapia Celular TerCel, Madrid, Spain

[7] Vall dHebron Hosp Universitari, Dept Hematol, Barcelona, Spain

[8] Univ Navarra, Computat Biol Program, Pamplona, Spain

[9] NavarraBiomed, Translat Bioinformat Unit, Pamplona, Spain

[10] King Abdullah Univ Sci & Technol, Biol & Environm Sci & Engn Div, Thuwal, Saudi Arabia

来源：

ELIFE | 2023年 / 12卷

基金：

欧盟地平线“2020”;

关键词：

hematopoietic stem; progenitor cells; aging; myelodysplastic syndrome; single-cell RNA sequencing; Human; DNA MICROARRAY ANALYSIS; HUMAN BONE-MARROW; GENE-EXPRESSION; STEM-CELLS; CLONAL HEMATOPOIESIS; ANALYSIS REVEALS; CD34(+) CELLS; IMMUNE; INDUCTION; PROGRAMS;

D O I：

10.7554/eLife.79363

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：28

共 68 条

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