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


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.

SUBMITTER: Renders S 

PROVIDER: S-EPMC7840807 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Renders Simon S   Svendsen Arthur Flohr AF   Panten Jasper J   Rama Nicolas N   Maryanovich Maria M   Sommerkamp Pia P   Ladel Luisa L   Redavid Anna Rita AR   Gibert Benjamin B   Lazare Seka S   Ducarouge Benjamin B   Schönberger Katharina K   Narr Andreas A   Tourbez Manon M   Dethmers-Ausema Bertien B   Zwart Erik E   Hotz-Wagenblatt Agnes A   Zhang Dachuan D   Korn Claudia C   Zeisberger Petra P   Przybylla Adriana A   Sohn Markus M   Mendez-Ferrer Simon S   Heikenwälder Mathias M   Brune Maik M   Klimmeck Daniel D   Bystrykh Leonid L   Frenette Paul S PS   Mehlen Patrick P   de Haan Gerald G   Cabezas-Wallscheid Nina N   Trumpp Andreas A  

Nature communications 20210127 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-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 endotheli  ...[more]

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