Biographie / Biography
Le Dr. Alexandre Dubrac a obtenu son doctorat à l’Université de Bordeaux I, où il a travaillé avec le Professeur Andreas Bikfalvi sur l’angiogénèse tumorale. Il s’est ensuite joint comme chercheur postdoctoral au groupe du Professeur Anne Eichmann à la Yale School of Medicine où il a exploré la fonction des régulateurs de guidance axonale lors du bourgeonnement des vaisseaux sanguins. Entre d’autres, ses travaux ont démontré la nouvelle fonction de Slit2 et Robo1&2 dans la néovascularisation de la rétine. Il a été chercheur associé à l’Université Yale, ou ses travaux ont porté sur l’interaction cellule entothéliale-péricyte au cours du développement vasculaire et de la rétinopathie ischémique. Le Dr. Dubrac a rejoint le CHU st-Justine en tant que chercheur adjoint sous octroi à l’Université de Montréal en 2018 et son laboratoire s’intéresse à identifier de nouveaux mécanismes régulant l’angiogenèse de la rétine et du cerveau lors du développement et dans des pathologies ischémiques.
Presentation
Noncanonical TGFb Signaling is Crucial for Specialized Neuroretina Tip-Cells Sprouting and Blood-Retina Barrier Formation
Georgia Zarkada1, Joel P. Howard2, Xue Xiao2,3, Mathilde Bizou2,3, Jinyu Li1, Martin Lange1, Severine Leclerc2, Steffen E. Künzel1, Gael Cagnone2, Jean Sebastien Joyal2, Gregor Andelfinger2, Anne Eichmann1,4#, Alexandre Dubrac2,3,5#
1Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; 2Centre de Recherche, CHU St. Justine, Montréal, QC, Canada; 3Département de pathologie et biologie cellulaire. Université de Montréal, Montréal, QC, Canada; 4Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA; 5Lead Contact
Endothelial sprouting and blood-retina barrier (BRB) are spatiotemporally and carefully orchestrated processes essential for neuroretina homeostasis and proper vision. Mouse retinal vascularization consists of two successive phases. The formation of the superficial vascular plexus is followed by vertical endothelial cell (EC) sprouting, which develops the deep neuroretina vascular layers and establishes the BRB. While these phases both involve VEGF-induced tip cell sprouting, it is not known how the deeper plexus can simultaneously sprout and establish the BRB. Here, using single cell RNA sequencing, we show that diving tip cells (D) constitute a distinct cell population that differs in gene expression and signaling requirements from the superficial tip cells (S). The tip cells D are ESM1– and Mfsd2a+, displaying BRB properties and a TGFb-induced gene signature. Genetic deletion of the TGFb receptor Alk5 in ECs (Alk5iEKO), predominantly affected tip cells D, which became hyperproliferative and hypercontractile, leading to the formation of hemorrhagic glomeruloid tufts and lack of the deep vascular layer. These vascular defects could be rescued by ROCK inhibition, but not cell cycle inhibitors or genetic activation of Wnt signaling. Endothelial deletion of the TGFb downstream SMAD2/3 or SMAD4 effectors did not recapitulate Alk5iEKO phenotypes, suggesting that noncanonical TGFb signaling is essential for neuroretina vascularization. Alk5iEKO mice displayed decreased retinal revascularization during oxygen-induced retinopathy. These data suggest that TGFb signaling could potentially be used therapeutically to promote retinal revascularization and improve neural function in individuals with ischemic retinopathy.