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

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-r...

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Veröffentlicht in:Nature communications 2021-01, Vol.12 (1), p.608-15, Article 608
Hauptverfasser: Renders, Simon, Svendsen, Arthur Flohr, Panten, Jasper, Rama, Nicolas, Maryanovich, Maria, Sommerkamp, Pia, Ladel, Luisa, Redavid, Anna Rita, Gibert, Benjamin, Lazare, Seka, Ducarouge, Benjamin, Schönberger, Katharina, Narr, Andreas, Tourbez, Manon, Dethmers-Ausema, Bertien, Zwart, Erik, Hotz-Wagenblatt, Agnes, Zhang, Dachuan, Korn, Claudia, Zeisberger, Petra, Przybylla, Adriana, Sohn, Markus, Mendez-Ferrer, Simon, Heikenwälder, Mathias, Brune, Maik, Klimmeck, Daniel, Bystrykh, Leonid, Frenette, Paul S., Mehlen, Patrick, de Haan, Gerald, Cabezas-Wallscheid, Nina, Trumpp, Andreas
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Sprache:eng
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Zusammenfassung: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. Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential and associated dormancy. Here the authors show that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1, and that decline of netrin-1 production during ageing leads to decreased Neo1 mediated HSC self-renewal.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-20801-0