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While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia\u2010specific Transforming Growth Factor\u2010\u03b2 (Tgf\u03b2) receptor knock out mouse model and human iPSC\u2010derived microglia to examine the role of Tgf\u03b2 signaling in activated microglia during retinal NV. Using a tamoxifen\u2010inducible, microglia\u2010specific Tgf\u03b2 receptor type 2 (Tgf\u03b2r2) knockout mouse [Tgf\u03b2r2 KO (\u0394MG)] we show that Tgf\u03b2 signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgf\u03b2 signaling represses expression of the pro\u2010angiogenic factor, Insulin\u2010like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen\u2010induced retinopathy (OIR) we show that Tgf\u03b2 signaling in activated microglia plays a role in hypoxia\u2010induced NV where a loss in Tgf\u03b2 signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC\u2010derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor\u2010\u03b21 (Tgf\u03b21) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgf\u03b2 signaling in microglia is essential for microglial homeostasis and that the disruption of Tgf\u03b2 signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression.<\/jats:p>","DOI":"10.1002\/glia.24218","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T11:30:51Z","timestamp":1653478251000},"page":"1762-1776","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Deletion of <scp>Tgf\u03b2<\/scp> signal in activated microglia prolongs hypoxia\u2010induced retinal neovascularization enhancing <scp>Igf1<\/scp> expression and retinal leukostasis"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2974-0830","authenticated-orcid":false,"given":"Ayumi","family":"Usui\u2010Ouchi","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine The Scripps Research Institute  La 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