TY - JOUR
T1 - Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1
AU - Renders, Simon
AU - Svendsen, Arthur Flohr
AU - Panten, Jasper
AU - Rama, Nicolas
AU - Maryanovich, Maria
AU - Sommerkamp, Pia
AU - Ladel, Luisa
AU - Redavid, Anna Rita
AU - Gibert, Benjamin
AU - Lazare, Seka
AU - Ducarouge, Benjamin
AU - Schönberger, Katharina
AU - Narr, Andreas
AU - Tourbez, Manon
AU - Dethmers-Ausema, Bertien
AU - Zwart, Erik
AU - Hotz-Wagenblatt, Agnes
AU - Zhang, Dachuan
AU - Korn, Claudia
AU - Zeisberger, Petra
AU - Przybylla, Adriana
AU - Sohn, Markus
AU - Mendez-Ferrer, Simon
AU - Heikenwälder, Mathias
AU - Brune, Maik
AU - Klimmeck, Daniel
AU - Bystrykh, Leonid
AU - Frenette, Paul S
AU - Mehlen, Patrick
AU - de Haan, Gerald
AU - Cabezas-Wallscheid, Nina
AU - Trumpp, Andreas
PY - 2021/1/27
Y1 - 2021/1/27
N2 - 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.
AB - 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.
KW - Animals
KW - Arterioles/metabolism
KW - Cell Differentiation
KW - Cell Proliferation
KW - Cellular Senescence
KW - Gene Deletion
KW - Hematopoietic Stem Cell Transplantation
KW - Hematopoietic Stem Cells/metabolism
KW - Membrane Proteins/metabolism
KW - Mice, Mutant Strains
KW - Mice, Transgenic
KW - Netrin-1/metabolism
KW - Signal Transduction
KW - Stem Cell Niche
U2 - 10.1038/s41467-020-20801-0
DO - 10.1038/s41467-020-20801-0
M3 - Article
C2 - 33504783
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 608
ER -