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Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1

Published version
Peer-reviewed

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Authors

Renders, Simon 
Svendsen, Arthur Flohr 
Panten, Jasper 

Abstract

Abstract: Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential associated to dormancy. Here we identify the cell surface receptor neogenin-1 as specifically expressed in dormant HSCs. Loss of neogenin-1 initially leads to increased HSC expansion but subsequently to loss of self-renewal and premature exhaustion in vivo. Its ligand netrin-1 induces Egr1 expression and maintains quiescence and function of cultured HSCs in a Neo1 dependent manner. Produced by arteriolar endothelial and periarteriolar stromal cells, conditional netrin-1 deletion in the bone marrow niche reduces HSC numbers, quiescence and self-renewal, while overexpression increases quiescence in vivo. Ageing associated bone marrow remodelling leads to the decline of netrin-1 expression in niches and a compensatory but reversible upregulation of neogenin-1 on HSCs. Our study suggests that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1 function. Decline of netrin-1 production during ageing leads to the gradual decrease of Neo1 mediated HSC self-renewal.

Description

Funder: Studienstiftung des Deutschen Volkes (German National Academic Foundation); doi: https://doi.org/10.13039/501100004350


Funder: Heinrich F.C. Behr Stiftung


Funder: Dietmar Hopp Stiftung; doi: https://doi.org/10.13039/501100005941

Keywords

Article, /631/443/7, /631/532/1542, /631/532/2441, /631/532/2139, /13/31, /38/91, /13/51, /13/100, /13/106, /14/19, /64/60, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

12

Publisher

Nature Publishing Group UK
Sponsorship
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (ERC-Stg-2017)
Deutsche Forschungsgemeinschaft (German Research Foundation) (FOR2033, SFB873)