Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1
Simon Renders
(1, 2, 3)
,
Arthur Flohr Svendsen
(4)
,
Jasper Panten
(1, 2, 5)
,
Nicolas Rama
(6, 7)
,
Maria Maryanovich
(8)
,
Pia Sommerkamp
(1, 2, 5)
,
Luisa Ladel
(1, 2)
,
Anna Rita Redavid
(6, 7)
,
Benjamin Gibert
(7, 6)
,
Seka Lazare
(4)
,
Benjamin Ducarouge
(7, 6)
,
Katharina Schönberger
(9)
,
Andreas Narr
(1, 2, 5)
,
Manon Tourbez
(4)
,
Bertien Dethmers-Ausema
(4)
,
Erik Zwart
(4)
,
Agnes Hotz-Wagenblatt
(1)
,
Dachuan Zhang
(8)
,
Claudia Korn
(10, 11)
,
Petra Zeisberger
(1, 2)
,
Adriana Przybylla
(1, 2)
,
Markus Sohn
(1, 2)
,
Simon Mendez-Ferrer
(10, 11)
,
Mathias Heikenwälder
(1)
,
Maik Brune
(3)
,
Daniel Klimmeck
(1, 2)
,
Leonid Bystrykh
(4)
,
Paul S Frenette
(8)
,
Patrick Mehlen
(7, 6)
,
Gerald de Haan
(4)
,
Nina Cabezas-Wallscheid
(9)
,
Andreas Trumpp
(1, 2, 12)
1
DKFZ -
German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
2 Heidelberg Institute for Stem Cell Technology and Experimental Medicine
3 Heidelberg University Hospital [Heidelberg]
4 University of Groningen [Groningen]
5 Universität Heidelberg [Heidelberg] = Heidelberg University
6 LabEx DEVweCAN - Développement Cancer et Thérapies Ciblées [Lyon]
7 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
8 Albert Einstein College of Medicine [New York]
9 MPI-IE - Max Planck Institute of Immunobiology and Epigenetics
10 CAM - University of Cambridge [UK]
11 NHS Blood and Transplant [London, UK]
12 DKTK - German Cancer Consortium [Heidelberg]
2 Heidelberg Institute for Stem Cell Technology and Experimental Medicine
3 Heidelberg University Hospital [Heidelberg]
4 University of Groningen [Groningen]
5 Universität Heidelberg [Heidelberg] = Heidelberg University
6 LabEx DEVweCAN - Développement Cancer et Thérapies Ciblées [Lyon]
7 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
8 Albert Einstein College of Medicine [New York]
9 MPI-IE - Max Planck Institute of Immunobiology and Epigenetics
10 CAM - University of Cambridge [UK]
11 NHS Blood and Transplant [London, UK]
12 DKTK - German Cancer Consortium [Heidelberg]
Nicolas Rama
- Fonction : Auteur
- PersonId : 761523
- ORCID : 0000-0003-1614-7755
Maria Maryanovich
- Fonction : Auteur
- PersonId : 814492
- ORCID : 0000-0002-2015-0538
Benjamin Gibert
- Fonction : Auteur
- PersonId : 739056
- IdHAL : benjamin-gibert
- ORCID : 0000-0002-5295-3124
- IdRef : 164111530
Erik Zwart
- Fonction : Auteur
- PersonId : 814493
- ORCID : 0000-0002-4552-003X
Dachuan Zhang
- Fonction : Auteur
- PersonId : 814494
- ORCID : 0000-0002-1746-275X
Simon Mendez-Ferrer
- Fonction : Auteur
- PersonId : 814495
- ORCID : 0000-0002-9805-9988
Mathias Heikenwälder
- Fonction : Auteur
- PersonId : 808383
- ORCID : 0000-0002-3135-2274
Leonid Bystrykh
- Fonction : Auteur
- PersonId : 814496
- ORCID : 0000-0001-6924-5602
Paul S Frenette
- Fonction : Auteur
- PersonId : 814497
- ORCID : 0000-0003-0862-9922
Patrick Mehlen
- Fonction : Auteur
- PersonId : 929874
- IdHAL : patrick-mehlen
- ORCID : 0000-0003-1743-5417
- IdRef : 069943524
Gerald de Haan
- Fonction : Auteur
- PersonId : 814498
- ORCID : 0000-0001-9706-0138
Nina Cabezas-Wallscheid
- Fonction : Auteur
- PersonId : 808101
- ORCID : 0000-0003-0870-0530
Résumé
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.
Domaines
Sciences du Vivant [q-bio]
Fichier principal
2021 Nat Comm Renders_et_al--published Nature_Communications.pdf (2.57 Mo)
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