biostudies-literatureMetz-Zumaran CDeutsche Forschungsgemeinschaft (DFG)Deutscher Akademischer AustauschdienstUF | UF Health | College of Medicine, University of FloridaDeutsche ForschungsgemeinschaftUF | UF Health | College of Medicine, University of Florida (UF College of Medicine)Chica and Heinz Schaller Foundation242-275https://www.ebi.ac.uk/biostudies/studies/S-EPMC10912784biostudies-literatureUnknown20(3)Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects their response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originating from epithelial tissues. Importantly, cells embedded witMolecular systems biologyThe population context is a driver of the heterogeneous response of epithelial cells to interferons.PMC10912784240245660278001972start-up packageBoulant SMetz-Zumaran CKuropka BFreund CUckeley ZMKuchenhoff LCavalcanti-Adam EAStanifer MKeser YRastgou Talemi SLukas PHofer TMuraca FGraw FDoldan PfalseThe population context is a driver of the heterogeneous response of epithelial cells to interferons.Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects their response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originating from epithelial tissues. Importantly, cells embedded wit2024-01-01T00:00:00Z2024 Mar2026-06-17T06:33:36.18Z2024-11-09T06:20:33.771ZS-EPMC109127843827316110.1038/s44320-024-00011-2