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Updated: Feb 26, 2026

In Vitro Three-Dimensional Sprouting Assay of Angiogenesis Using Mouse Embryonic Stem Cells for Vascular Disease Modeling and Drug Testing
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Sema3F (Semaphorin 3F) Selectively Drives an Extraembryonic Proangiogenic Program.

Donatella Regano1, Alessia Visintin1, Fabiana Clapero1

  • 1From the Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Torino, Italy (D.R., A.V., F.C., F.B., D.V., F.M., G.S., E.G.); Department of Science and Drug Technology, University of Torino, Italy (D.R., A.V., F.M., E.G.); and Department of Oncology, University of Torino School of Medicine, Candiolo, Italy (F.C., F.B., D.V., G.S.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|July 22, 2017
PubMed
Summary

Class 3 semaphorin F (Sema3F) unexpectedly promotes extraembryonic blood vessel development. It inhibits Myc degradation, reducing antiangiogenic thrombospondin 1 (Thbs1) synthesis in yolk sac cells.

Keywords:
angiogenesis modulating agentsmicemycsemaphorinsthrombospondinsyolk sac

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Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Angiogenesis Research

Background:

  • Blood vessel patterning is crucial for vertebrate development.
  • Class 3 semaphorins (Sema3) are known antiangiogenic factors regulating embryonic vascular morphogenesis.
  • The role of Sema3 in extraembryonic vascular development remains unexplored.

Purpose of the Study:

  • To investigate the function of Sema3 in extraembryonic vascular development.
  • To elucidate the molecular mechanisms by which Sema3 influences angiogenesis in the visceral yolk sac.
  • To determine if Sema3F acts as a proangiogenic or antiangiogenic factor in extraembryonic tissues.

Main Methods:

  • Characterization of genetically modified mice (Sema3f-null).
  • In vivo and in vitro studies using visceral yolk sac epithelial cells.
  • Analysis of Myc, microRNA 17/92 cluster, thrombospondin 1 (Thbs1), and vascular endothelial growth factor (Vegf) signaling.
  • Experiments with mouse F9 teratocarcinoma stem cells.

Main Results:

  • Sema3F acts as a selective proangiogenic cue for extraembryonic, but not intraembryonic, vasculature.
  • Sema3F inhibits phosphorylation-dependent degradation of Myc in visceral yolk sac epithelial cells.
  • Sema3f deficiency leads to impaired Myc-regulated microRNA 17/92, increased Thbs1 synthesis, and inhibited Vegf signaling.
  • Sema3f-null mice exhibit anemic and abnormally vascularized placentas.

Conclusions:

  • Sema3F functions as an unconventional Class 3 semaphorin.
  • Sema3F promotes extraembryonic angiogenesis.
  • This promotion occurs via inhibition of Myc-regulated Thbs1 synthesis in visceral yolk sac epithelial cells.