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

  • 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
  • And 12 more
Publication Date
Jan 21, 2021
Apollo - University of Cambridge Repository
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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. / We thank all technicians of the Trumpp, Mehlen and de Haan laboratories for technical assistance; S. Schmitt, M. Eich, K. Hexel, T. Rubner from the DKFZ Flow Cytometry Core, and W. Abdulahad, T. Bijma, G.Mesander and J. Teunis from UMCG Flowcytometry Unit facilities for their assistance; K. Reifenberg, P. Prückl, M. Schorpp-Kistner, A. Rathgeb and all members of the DKFZ and UMCG Laboratory Animal Core Facility for excellent animal welfare and husbandry. We thank the DKFZ and ERIBA Genomics and Proteomics Core Facility for their assistance. This work was supported by the Heinrich F.C. Behr foundation, Studienstiftung des deutschen Volkes (S.R), by INCA, ERC, ANR and Fondation Bettencourt (all to P.M.), Max Planck Society and the ERC-Stg-2017 (VitASTEM) (all to N.C-W), the FOR2033 and SFB873 funded by the Deutsche Forschungsgemeinschaft (DFG) and the Dietmar Hopp Foundation (all to A.T). Studies in the Frenette laboratory were funded by the National Institutes of Health (DK056638, HL069438, HL116340 to P.S.F.). M.M. is a New York Stem Cell Foundation (NYSCF) Druckenmiller fellow. Studies in the de Haan laboratory were funded by the Netherlands Organization for Scientific Research/Mouse Clinic for Cancer and Ageing, the Landsteiner Foundation for Blood Transfusion Research (LSBR1703), and Marriage, a EU FP7 Marie Curie Initial Training Network (Contract number 316964).

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