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Drusen are key contributors to the etiology of AMD and the ability to modulate drusen biogenesis could lead to therapeutic strategies to slow or halt AMD progression. The mechanisms underlying drusen biogenesis, however, remain mostly unknown. Here we demonstrate that under homeostatic conditions extracellular vesicles (EVs) secreted by retinal pigment epithelium (RPE) cells are enriched in proteins associated with mechanisms involved in AMD pathophysiology, including oxidative stress, immune response, inflammation, complement system and drusen composition. Furthermore, we provide first evidence that drusen\u2010associated proteins are released as cargo of extracellular vesicles secreted by RPE cells in a polarised apical:basal mode. Notably, drusen\u2010associated proteins exhibited distinctive directional secretion modes in homeostatic conditions and, differential modulation of this directional secretion in response to AMD stressors. These observations underpin the existence of a finely\u2010tuned mechanism regulating directional apical:basal sorting and secretion of drusen\u2010associated proteins via EVs, and its modulation in response to mechanisms involved in AMD pathophysiology. Collectively, our results strongly support an active role of RPE\u2010derived EVs as a key source of drusen proteins and important contributors to drusen development and growth.<\/jats:p>","DOI":"10.1002\/jev2.12165","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T23:42:38Z","timestamp":1636414958000},"source":"Crossref","is-referenced-by-count":86,"title":["Extracellular vesicles released by human retinal pigment epithelium mediate increased polarised secretion of drusen proteins in response to AMD stressors"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3421-3699","authenticated-orcid":false,"given":"Miguel","family":"Flores\u2010Bellver","sequence":"first","affiliation":[{"name":"<i>CellSight<\/i> Ocular Stem Cell and Regeneration Program Department of Ophthalmology Sue Anschutz\u2010Rodgers Eye Center University of Colorado, School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Mighty","sequence":"additional","affiliation":[{"name":"Lehman College  Bronx New York USA"},{"name":"Biology Doctoral Program The Graduate School and University Center City University of New York  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Aparicio\u2010Domingo","sequence":"additional","affiliation":[{"name":"<i>CellSight<\/i> Ocular Stem Cell and Regeneration Program Department of Ophthalmology Sue Anschutz\u2010Rodgers Eye Center University of Colorado, School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang V.","family":"Li","sequence":"additional","affiliation":[{"name":"<i>CellSight<\/i> Ocular Stem Cell and Regeneration Program Department of Ophthalmology Sue Anschutz\u2010Rodgers Eye Center University of Colorado, School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cui","family":"Shi","sequence":"additional","affiliation":[{"name":"Lehman College  Bronx New York USA"},{"name":"Biology Doctoral Program The Graduate School and University Center City University of New York  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Lehman College  Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Cobb","sequence":"additional","affiliation":[{"name":"<i>CellSight<\/i> Ocular Stem Cell and Regeneration Program Department of Ophthalmology Sue Anschutz\u2010Rodgers Eye Center University of Colorado, School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"McGrath","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Michelis","sequence":"additional","affiliation":[{"name":"Section of Protein Structure and Function NEI NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Lenhart","sequence":"additional","affiliation":[{"name":"<i>CellSight<\/i> Ocular Stem Cell and Regeneration Program Department of Ophthalmology Sue Anschutz\u2010Rodgers Eye Center University of Colorado, School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganna","family":"Bilousova","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of Colorado School of Medicine  Aurora Colorado USA"},{"name":"Charles C. 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