Retinal blood vessel-origin yes-associated protein (YAP) governs astrocytic maturation via leukaemia inhibitory factor (LIF).
OBJECTIVES
To testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion.


MATERIALS AND METHODS
In vivo experiments, mice bearing floxed alleles of YAP were crossed with mice expressing a Cre recombinase driven by the endothelial Tek promoter (Tek-Cre) to finally obtain the following three genotypes: YAPf/f , Tek-Cre; YAPf/w , Tek-Cre; and YAPf/f . Retinal vascularization and astrocyte network were evaluated by whole-mount fluorescence and Western blotting. In vitro, experiments were performed in an astrocyte and human microvascular endothelial cell (HMEC-1) coculture model to analyse the mechanisms underlying the effect of endothelial YAP on astrocytes.


RESULTS
In vivo, YAPf/f ;Tek-Cre mice showed delayed angiogenesis, sparse vessels and decreased glial fibrillary acidic protein (GFAP)+ astrocytes but aberrant growth of endothelial networks and immature astrocytes (platelet-derived growth factor A, PDGFRA+ astrocytes) overgrowth. In vitro, Yap deletion attenuated the LIF release that delayed the maturation of retinal astrocyte which was consistent with the results of HMEC-1-astrocyte coculture. The effect of YAP overexpression on LIF-LIFR axis in HMEC-1 interferes the GFAP expression of astrocyte. In contrast, LIF protein rescues the astrocytic GFAP expression when EC YAP was inhibited by siRNAs.


CONCLUSIONS
We show that EC yes-associated protein (YAP) is not only a critical coactivator of Hippo signalling in retinal vessel development but also plays an essential role in retinal astrocyte maturation by regulating LIF production.
['Ai|Li-Qian-Yu|LQ|https://orcid.org/0000-0001-6433-6476', 'Yuan|Rong-Di|RD|', 'Chen|Xi|X|', 'Liu|Yun-Jia|YJ|', 'Liu|Wen-Yi|WY|', 'Zhu|Jing-Yi|JY|', 'Zhang|Zhou|Z|', 'Yan|Jun|J|', 'Chen|Chun-Lin|CL|', 'Lin|Sen|S|https://orcid.org/0000-0001-9346-8187', 'Ye|Jian|J|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D001253:Astrocytes D002454:Cell Differentiation D049109:Cell Proliferation D018920:Coculture Techniques D042783:Endothelial Cells D005260:Female D005904:Glial Fibrillary Acidic Protein D006801:Humans D053605:Leukemia Inhibitory Factor D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009389:Neovascularization, Pathologic D018919:Neovascularization, Physiologic D055495:Neurogenesis D012160:Retina D012171:Retinal Vessels D014157:Transcription Factors D000091102:YAP-Signaling Proteins
yes-associated protein leukaemia inhibitory factor retinal vessel development astrocyte premature