Thread by @Giulsboezio

I'm thrilled to share our story about the cellular crosstalk in the developing heart, regulated by TGF-β from the endothelial cells. Below more details and some beautiful #zebrafish hearts ⬇️. Coincidentally, it was out @elife exactly on #WorldHeartDay! ❤️elifesciences.org/articles/57603

When we mutated tgfbr1/alk5 in zebrafish, we found a very specific dilation of the cardiac outflow tract (OFT), resembling mammal aortic aneurysms...while all the other vessels and the heart looked unaffected. Occasionally, we even found ruptures and holes in the OFT!

In contrast with the literature on aneurysms and on TGF-β (focus on smooth muscle cells), we observed that the earliest defect in the increased proliferation of endothelial cells, when we did not even observe any morphological defect yet. Is it here where Alk5 plays a role?

Later on, the alk5 mutant OFT is also covered by fewer smooth muscle cells (SMCs) than WT and surrounded by impaired extracellular matrix (ECM, see below elastin in white). But where is Alk5 necessary then? In which cell type?

On 02/10/2018 (aka the best day of my PhD😉), we surprisingly found that Alk5 was sufficient in ECs to drive the correct morphogenesis of the OFT! When we overexpressed the alk5 in ECs in the mutants, we completely rescued the phenotype (even the SMC one).

Then, we asked how is this signal transferred from ECs to SMCs and we found that the ECM is an extraordinary platform for communication also in the OFT.

We also found that re-overexpressing Fbln5, a very specific OFT ECM protein, from the ECs can partially rescue the phenotype.
Take home message, endothelial cells are crucial in OFT development...and potentially in aortic malformations too!

This was a challenging but fantastic project that taught me more than I could ever imagine. Seeing it out is an incredible feeling, for which I cannot thank enough the #Stainierlab, in which I found colleagues, supporters and friends, and Didier in particular for the guidance. ❤️

Some more huge "Thank you" are due. First, to my fantastic coauthor (@BensimonBrito and the ones not on Twitter) for sharing the journey and helping a lot.

Second, to @elife for a GREAT experience. In particular, I would like to thank the editors (E. Morrisey and @MeilhacSigolene ) and the reviewers (@julien_vermot and M. Azhar) for the constructive review process that incredibly improved the manuscript. It was REALLY a pleasure!🥳

Wait a minute!😋 I can share here my favorite 3D video, which never made it into the paper! Here a zebrafish cardiac OFT and connecting vessels, with blood cells (red) running around :)