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 Zeisberger, Adriana 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 () and Andreas Trumpp ()
Additional contact information
Simon Renders: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Arthur Flohr Svendsen: University Medical Center Groningen, University of Groningen
Jasper Panten: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Nicolas Rama: Centre Léon Bérard
Maria Maryanovich: Albert Einstein College of Medicine
Pia Sommerkamp: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Luisa Ladel: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Anna Rita Redavid: Centre Léon Bérard
Benjamin Gibert: Centre Léon Bérard
Seka Lazare: University Medical Center Groningen, University of Groningen
Benjamin Ducarouge: Centre Léon Bérard
Katharina Schönberger: Max Planck Institute of Immunobiology and Epigenetics
Andreas Narr: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Manon Tourbez: University Medical Center Groningen, University of Groningen
Bertien Dethmers-Ausema: University Medical Center Groningen, University of Groningen
Erik Zwart: University Medical Center Groningen, University of Groningen
Agnes Hotz-Wagenblatt: German Cancer Research Center (DKFZ)
Dachuan Zhang: Albert Einstein College of Medicine
Claudia Korn: University of Cambridge
Petra Zeisberger: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Adriana Przybylla: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Markus Sohn: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Simon Mendez-Ferrer: University of Cambridge
Mathias Heikenwälder: German Cancer Research Center Heidelberg (DKFZ)
Maik Brune: Heidelberg University Hospital
Daniel Klimmeck: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Leonid Bystrykh: University Medical Center Groningen, University of Groningen
Paul S. Frenette: Albert Einstein College of Medicine
Patrick Mehlen: Centre Léon Bérard
Gerald de Haan: University Medical Center Groningen, University of Groningen
Nina Cabezas-Wallscheid: Max Planck Institute of Immunobiology and Epigenetics
Andreas Trumpp: German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance

Nature Communications, 2021, vol. 12, issue 1, 1-15

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.

Date: 2021
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DOI: 10.1038/s41467-020-20801-0

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