05:16am Monday 13 July 2020

New insights in sprouting angiogenesis

What do tip cells and stalk cells do?
Tip and stalk cells make up newly forming bloodvessel sprouts, with the tip cell being the leading
cell that is specialized for guided migration, and the stalk cells following the tip, shaping the lumen
and supporting growth. Both tip and stalk cells are endothelial cells that are activated by growth factors.

Previous work has shown that the balance of tip and stalk cell numbers is important for shaping the density and pattern of newly forming blood vessel networks, and that this balance is regulated by Notch signalling.

Your research is focused on how Notch does this. Can you elaborate?
Our earlier discovery that all endothelial cells form tip cells when Notch is turned off suggested that the tip cell phenotype is the default response of endothelial cells to the activation by growth factors. This concept has transformed the field in many ways as it stimulated further work into the principles of endothelial cell specification and on the genetic network surrounding Notch activity, including new discoveries in vascular malformation in disease and potential tip cell-targeted therapeutic approaches.

Now we have identified the first true downstream effector of Notch, Neuropilin1 (Nrp1). Endothelial cells with too little Nrp1 cannot make tip cells even when Notch is turned off. We have also shown that the TGFb signalling pathway needs to be down-regulated to allow tip cell formation, and that Nrp1 is critical for this down-modulation.

You show that the stak-cell phenotype needs to be repressed to allow tip-cell formation, how is
knowing this relevant?
It allows a new perspective on how we might develop therapies that either stimulate or inhibit formation of new tip cells. There is strong evidence that vascular malformations can be triggered by defects in the TGFb pathway, and our newly discovered link between Nrp1 and TGFb signalling in the endothelium suggests that targeting Nrp1 could be a novel opportunity to treat
such vascular complications.

These insights are the results of a fruitful collaboration…
Indeed, this work has developed into a fantastic collaboration of my integrated team between the
London Research Institute and VIB/KU Leuven, with the group of Anne Eichmann (Yale School of Medicine, US). At a conference, we discovered that we had highly complementary data and tools.

The original discovery of the importance of Nrp1 levels for tip cell competition independent of Notch but through TGFb, was made in our lab. At the same time, using genetic compound mutant mice, Eichmann’s team had found that Npr1 deficient cells do not make tip cells. Our link to TGFb could be ideally studied through the TGFb and BMP signalling mutants in her lab.

The work and the emerging concepts have motivated us to build on this interaction. We are now developing a network of teams to both deepen our understanding of the mechanism and translate the concept into clinical benefit.

Aspalter et al., Nat Communications 2015

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