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

Simon Renders, Arthur Flohr Svendsen, Jasper Panten, Nicolas Rama, Maria Maryanovich, Pia Sommerkamp, Luisa Ladel, Anna Rita Redavid, Benjamin Gibert, Seka Lazare, Benjamin Ducarouge, Katharina Schönberger, Andreas Narr, Manon Tourbez, Bertien Dethmers-Ausema, Erik Zwart, Agnes Hotz-Wagenblatt, Dachuan Zhang, Claudia Korn, Petra ZeisbergerAdriana Przybylla, Markus Sohn, Simon Mendez-Ferrer, Mathias Heikenwälder, Maik Brune, Daniel Klimmeck, Leonid Bystrykh, Paul S. Frenette, Patrick Mehlen, Gerald de Haan, Nina Cabezas-Wallscheid, Andreas Trumpp

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number608
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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