title: Reciprocal epithelial:endothelial paracrine interactions during thyroid development govern follicular organization and C-cells differentiation.
abstract: The thyroid is a highly vascularized endocrine gland, displaying a characteristic epithelial organization in closed spheres, called follicles. Here we investigate how endothelial cells are recruited into the developing thyroid and if they control glandular organization as well as thyrocytes and C-cells differentiation. We show that endothelial cells closely surround, and then invade the expanding thyroid epithelial cell mass to become closely associated with nascent polarized follicles. This close and sustained endothelial:epithelial interaction depends on epithelial production of the angiogenic factor, Vascular Endothelial Growth Factor-A (VEGF-A), as its thyroid-specific genetic inactivation reduced the endothelial cell pool of the thyroid by > 90%. Vegfa KO also displayed decreased C-cells differentiation and impaired organization of the epithelial cell mass into follicles. We developed an ex vivo model of thyroid explants that faithfully mimicks bilobation of the thyroid anlagen, endothelial and C-cells invasion, folliculogenesis and differentiation. Treatment of thyroid explants at e12.5 with a VEGFR2 inhibitor ablated the endothelial pool and reproduced ex vivo folliculogenesis defects observed in conditional Vegfa KO. In the absence of any blood supply, rescue by embryonic endothelial progenitor cells restored folliculogenesis, accelerated lumen expansion and stimulated calcitonin expression by C-cells. In conclusion, our data demonstrate that, in developing mouse thyroid, epithelial production of VEGF-A is necessary for endothelial cells recruitment and expansion. In turn, endothelial cells control epithelial reorganization in follicles and C-cells differentiation.
authors.affiliation: de Duve Institute, Université catholique de Louvain (UCL), B-1200 Brussels, Belgium.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Hick
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Delmarcelle
authors.forename: Mahé
authors.initials: M
authors.lastname: Bouquet
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klotz
authors.forename: Tamara
authors.initials: T
authors.lastname: Copetti
authors.forename: Celine
authors.initials: C
authors.lastname: Forez
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Der Smissen
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Collet
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000378:metabolism; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000166:cytology*; D004727:Endothelium / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology; D013961:Thyroid Gland / Q000098:blood supply / Q000196:embryology* / Q000254:growth & development; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D002116:Calcitonin; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: C-cells; Endothelium; Epithelium; Explants; Follicles; Paracrine control; Polarity; Thyroid; VEGF-A