Salama Yousef, Hattori Koichi, Heissig Beate
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Center for Genome and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Biochem Biophys Res Commun. 2017 Aug 19;490(2):209-216. doi: 10.1016/j.bbrc.2017.06.023. Epub 2017 Jun 8.
Thymic regeneration is a crucial function that allows for the generation of mature T cells after myelosuppression like irradiation. However molecular drivers involved in this process remain undefined. Here, we report that the angiogenic factor, epidermal growth factor-like domain 7 (Egfl7), is expressed on steady state thymic endothelial cells (ECs) and further upregulated under stress like post-irradiation. Egfl7 overexpression increased intrathymic early thymic precursors (ETPs) and expanded thymic ECs. Mechanistically, we show that Egfl7 overexpression caused Flt3 upregulation in ETPs and thymic ECs, and increased Flt3 ligand plasma elevation in vivo. Selective Flt3 blockade prevented Egfl7-driven ETP expansion, and Egfl7-mediated thymic EC expansion in vivo. We propose that the angiogenic factor Egfl7 activates the Flt3/Flt3 ligand pathway and is a key molecular driver enforcing thymus progenitor generation and thereby directly linking endothelial cell biology to the production of T cell-based adaptive immunity.
