ABSTRACT
Background Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate and are primed toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we evaluated human HSPCs obtained from young and elderly healthy donors using single-cell RNA sequencing to identify the transcriptional and regulatory perturbations associated with healthy aging at single cell resolution. We then applied this knowledge to identify specific changes associated with the development of myeloid malignancies.
Results Based on the transcriptional profile obtained, 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 aberrant 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 the previous findings as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome and acute myeloid leukemia and detected an alteration of the expression dynamics of genes involved in erythroid differentiation and identified specific transcription factors deregulated in acute myeloid leukemia.
Conclusions We demonstrate that the combination of single cell technologies and computational tools enables the study of a variety of cellular mechanisms involved in early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Email addresses
Marina Ainciburu mainciburu{at}alumni.unav.es
Teresa Ezponda tezponda{at}unav.es
Nerea Berastegui nberastegui{at}alumni.unav.es
Ana Alfonso-Pierola aalfonso{at}unav.es
Amaia Vilas-Zornoza avilaszo{at}unav.es
Patxi San Martin-Uriz psanmart{at}unav.es
Diego Alignani dalignani{at}unav.es
Jose Lamo de Espinosa jlamodeespi{at}unav.es
Mikel San Julian msjulian{at}unav.es
Tamara Jimenez tamara_js{at}usal.es
Félix López flcadenas{at}saludcastillayleon.es
Sandra Muntion smuntion{at}usal.es
Fermín Sanchez-Guijo ferminsg{at}usal.es
Antonieta Molero amolero{at}vhio.net
Julia Montoro jmontoro{at}vhio.net
Guillermo Serrano gserranos{at}unav.es
Aintzane Diaz-Mazkiaran adiazma{at}unav.es
Miren Lasaga mlagasag{at}unav.es
David Gomez-Cabrero david.gomez.cabrero{at}navarra.es
María Díez-Campelo mdiezcampelo{at}usal.es
David Valcarcel dvalcarcel{at}vhio.net
Mikel Hernaez mhernaez{at}unav.es
Juan P. Romero jromeror{at}unav.es
Felipe Prosper fprosper{at}unav.es
Institutional addresses
CIMA Av. de Pío XII, 55, 31008 Pamplona, Navarra, Spain
Clínica Universidad de Navarra Av. de Pío XII, 36, 31008 Pamplona, Navarra, Spain
University of Navarra Campus Universitario, 31009 Pamplona, Navarra,Spain
Hospital Universitario de Salamanca-IBSAL, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.
University Hospital Vall d’Hebron Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain
NavarraBiomed Calle de Irunlarrea, 3, 31008 Pamplona, Navarra, Spain
List of abbreviations used
- AML
- Acute myeloid leukemia
- AUC
- Area under the curve
- GRN
- Gene regulatory network
- GSEA
- Gene set enrichment analysis
- HSC
- Hematopoietic stem cell
- HSPC
- Hematopoietic stem and progenitor cell
- PCA
- Principal component analysis
- RSS
- Regulon specificity score
- scRNA-seq
- Single Cell RNA Sequencing
- UMI
- Unique molecular identifier