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Netrin-1 regulates haematopoietic stem cells

Presented by
Dr Simon Renders, German Cancer Research Centre, Germany
EHA 2020
Using murine models, the ligand/receptor pair Netrin-1/Neogenin is identified as novel signalling axis in bone marrow niches. The role of Netrin-1/Neogenin in maintenance of haematopoietic stem cell (HSC) dormancy and rejuvenation may possibly occur through periarteriolar cells.

By performing DNA-methylome, proteome, as well as single-cell RNA-sequencing analyses on multipotent progenitor (MPP) populations and dormant/active HSCs in mouse models, Dr Simon Renders (German Cancer Research Centre, Germany) and colleagues found distinct and high expression of the Neogenin (Neo1) receptor in dormant HSCs [1]. Neo1 expression is increased in aged HSCs, as well. Neo1 was first described as an axon guidance factor that binds neural guidance molecules including Netrin-1 (Ntn1). The hypothesis tested in murine models was whether Neo1 and its ligands may preserve HSC dormancy, self-renewal, and function.

Using murine gene editing, conditional deletion of Ntn1 in bone marrow niche cells was observed to cause a depletion of HSCs associated to signs of activation and premature differentiation. Ntn1is produced by arteriolar endothelial and peri-arteriolar stromal cells within the bone marrow niche and its expression becomes diminished upon aging.

To investigate Neo1 function, a population of co-existing Neo+ and Neo- cells in Neo1-mutant chimaeric mice were studied. Cellular data from this population suggested that ageing caused a myeloid differentiation bias, reduced overall HSC numbers, and resulted in a robustly reduced engraftment potential. Collectively, these data suggest a role for Neo1 in preserving HSC dormancy and preventing premature ageing.

In vitro and in vivo studies supported this hypothesis. Both the addition of recombinant Ntn1 to standard HSC culture conditions increased HSCs engraftment after transplantation compared with untreated control cells. Accordingly, loss of Ntn1 expressed by HSC niche cells using 2 different inducible knock-out mice resulted in depletion of HSCs.

Ntn1/Neo1 is a novel ligand-receptor pair regulating HSC quiescence and long-term self-renewal, which is altered during aging and is a novel signalling axis linking periarteriolar cells to HSCs. The Ntn1/Neo1 axis promotes dormancy and HSC maintenance, while disruption leads to cell cycle activation, loss of self-renewal, and HSC exhaustion. The Ntn1/Neo1 axis weakens upon physiological ageing, inducing age-dependent changes of HSCs and may offer a molecular target for HSC rejuvenation.

    1. Renders S, et al. Netrin-1 regulates hematopoietic stem cell dormancy and function via its receptor neogenin with implications for stem cell ageing. EHA25 Virtual, 11-21 June 2020, Abstract S103.

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