Tammy C. T. Lan, Alison Kochersberger, Ruth Raichur, Sophia Szady, Hien Tran, Radiana Simeonova, Ashley Helmuth, Andrew Minagar, María Martín Fuentes, Vipin Kumar, Giovanni Marrero, Irving Barrera, Sarah Mangiameli, Alex K. Shalek, Pardis C. Sabeti, Fei Chen, David S. Fischer, Jennifer L. Garrison, Hattie Chung
Throughout the female reproductive lifespan, the ovary undergoes hundreds of cycles of follicle development, ovulation and tissue regeneration. How aging disrupts the coordination of such precise, multicellular interactions across time and space is not well understood. Using Slide-seq, a near-cellular spatial transcriptomics method, here we profile 22 mouse ovaries across the reproductive cycle and chronological ages, capturing 610,620 spots across 69 spatial profiles. We develop a novel segmentation pipeline to examine the multicellular dynamics of 358 oocytes, 668 follicles and 236 corpora lutea to find that aging impairs the spatial and temporal coordination required for folliculogenesis even before reproductive cycles cease. These disruptions are characterized by altered immune cell dynamics, inflammatory signaling and global tissue disorganization, which impair the cyclic remodeling required for ovarian function. Our findings reveal how multicellular niches orchestrate ovarian function and demonstrate that age-related breakdown in tissue organization precedes the end of fertility.