Identification and functional characterization of hematopoietic stem cell aging genes
Description: Stem cell exhaustion is one of the key hallmarks of aging. All blood cells in the circulation are derived from a rare population of hematopoietic stem cells (HSCs), that maintain homeostasis of blood cell production during the lifespan of an organism. During aging, the functional capacity of HSCs declines, which manifests in an array of clinically relevant phenotypes, such as impaired immunity, cytopenias, myelodysplastic syndromes and leukemias. Although multiple studies, including those from our lab, have revealed the involvement of several molecular mechanisms that are associated with HSC aging, the identification of individual genes that contribute to the phenotype of aged HSC has remained challenging. Using a meta-analysis of published and unpublished murine HSC aging transcriptome data we have recently documented that aged HSCs show a distinct gene expression profile, characterized by upregulation of many cell surface molecules, many of which have no known role in HSC biology. The HSC aging signature that we uncovered consists of 220 genes whose expression is consistently different between young and aged HSCs. In the present application we propose to:
1. Reveal the involvement of epigenetic mechanisms that result in aberrant expression of HSC aging genes.
2. Isolation and molecular and functional characterization of single aged HSCs using newly identified cell surface markers.
3. Improve the functioning of aged HSC by genetic intervening in key aging pathways.
This project will provide molecular insight into pathways that contribute to HSC aging, and will reveal whether it is possible to improve the functioning of aged HSCs. We anticipate that this knowledge will of value in exploring anti-aging strategies to prevent hematological disease.
Funding type: grant
Funder scheme: Open Competitie ENW - M 2020/2021 M20-1
Start date: 2022-03-01
Investigator: Gerald Haan
Institution: Universitair Medisch Centrum Groningen
Funded outputs count: 3
Funder award ID: OCENW.M20.002
OpenAlex ID: G1279354568