Regulating haematopoietic stem cell dormancy and ageing through the netrin-1-neogenin axis

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Published: 13 Jun 2020
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Dr Simon Renders - German Cancer Research Center (DKFZ), Heidelberg, Germany

Dr Simon Renders speaks to ecancer about the study he presented during the presidential symposium at the EHA 2020 virtual meeting.

He summarises the background of the study, which identified netrin-1 as a regulator of haematopoietic stem cell dormancy and function through its receptor, neogenin.

Dr Renders also explains the implications this pathway could have for stem cell ageing, along with the methods used for this study.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Here at Hi-STEM I work in the group of Andreas Trumpp and we’ve always been interested in quiescence and dormancy. So features of stem cells that allow them to not take part in steady state everyday blood production but maintain essentially sleeping in the bone marrow and then to be reactivated in cases of dire need for blood or immune cells, essentially infections or blood loss. This is a very unique feature in stem cell systems, for example in the gut stem cells are usually not considered to be quiescent, and it’s very tightly regulated by intra- and extracellular mechanisms. We are trying to elucidate them and I’m going to present one new pathway that maintains stem cell quiescence in the hematopoietic system.

What was the main hypothesis?

The hypothesis is that this process of maintaining stem cells in quiescence essentially is really essential for keeping stem cells alive during the whole lifetime of a mouse. If stem cells are not kept in quiescence they will be functionally inferior. Additionally, we focus on the question of whether the mechanisms that maintain stemness during the normal life, during the early lifespan of a mouse or a human being, are altered in aged people and therefore can explain why the immune system of older people or mice are worse off than the ones of young animals.

What were the methods?

We used mostly transgenic mice and RNA sequencing to identify our targets and then transgenic mice to functionally study whether the molecules that we find in our screening are relevant. We identified a receptor, it’s called neogenin, which is specifically expressed on hematopoietic stem cells and really on the most quiescent hematopoietic stem cells.
If you look further to the progenitor cells which are limited in their functional capabilities, this receptor is not expressed any more. Therefore we were quite excited that there might be a unique molecule that is only expressed on the most potent stem cells and we’re wondering about the different ligands, in this case netrins and repulsive guidance molecules, molecules that have originally been identified in brain biology. So those molecules usually regulate the sprouting of neurons throughout the brain and now we find this molecular signalling hub in hematopoietic stem cells. Then we started to use plenty of different transgenic mice that allow us to overexpress or knock out netrins, and neogenin is their receptor, in the hematopoietic system and in the microenvironment surrounding hematopoietic stem cells.

What were the main results?

We find that if we knock out either netrin, so the ligand of neogenin, or neogenin the functional capabilities of hematopoietic stem cells are impaired. That is the first big important thing. The second thing is that they lose their quiescence, so they get activated more, they cycle more. If you then transplant them into a secondary recipient they cannot engraft as well as normal non-transgenic hematopoietic stem cells in either system.
Additionally we find that if we culture stem cells in vitro and we stimulate them additionally with netrin-1, so the ligand of neogenin, we can increase the engraftment capability of cultured hematopoietic stem cells which is an important point considering transplant settings.

Is there anything you’d like to add?

One last important point is that we find if we look at aged mice then we see that normal aging, the normal process of physiological aging, is deregulating, disrupting the expression of neogenin ligands, especially netrins. We think that this, in combination with the disruption of the expression of other molecules that are essential for hematopoietic stem cell maintenance, like stem cell factor for example, CXCL12 (?) is an important factor of hematopoietic stem cell dysfunction in aged patients and for netrin it’s similar. So therefore we think that we can contribute to the biology of hematopoietic stem cell aging in a way and that we think that aging is more an extrinsic process. So the microenvironment is changing and that changes the hematopoietic stem cells.