Multicellular origins of ovarian inflammaging [Spatial Transcriptomics]

Age-dependent reproductive decline has become a significant global health concern as the average maternal age at first birth increases. Fertility loss associated with reproductive aging is driven in part by alterations to ovarian composition and function, dysregulation of folliculogenesis and increased inflammatory signaling. Our understanding of the molecular changes underlying ovarian aging has been expanded by single cell and spatial transcriptomic studies, which identified infiltration of immune cells as a feature of ovarian aging. However, the function of these age-associated immune cells and their potential contributions to the inflammaging phenotype remains unclear. In this study we integrate single cell and spatial transcriptomics to define changes in the composition and intercellular signaling in the aging mouse ovary. We identify specific macrophage and T cell subpopulations that increase with age and are key sources of pro-inflammatory signaling in old ovaries. Further, we predict bidirectional signaling between these pro-inflammatory cells and granulosa cell populations that may impair follicular growth and development while promoting immune cell recruitment. These findings provide new insights into the mechanisms that drive ovarian inflammaging. Spatial transcriptomics was performed on histological sections of whole ovaries isolated from 2 month old and ~14 month old C57BL6/J female mice. Slide-seq随着首次生育产妇的平均年龄逐年攀升，年龄依赖性生殖衰退已成为全球范围内不容忽视的公共健康问题。与生殖衰老相关的生育力损失，部分源于卵巢组成与功能的改变、卵泡发生调控失常以及炎症信号通路的过度激活。单细胞及空间转录组学（spatial transcriptomics）研究拓展了我们对卵巢衰老潜在分子机制的认知，此类研究已证实免疫细胞浸润是卵巢衰老的典型特征。然而，这类年龄相关性免疫细胞的具体功能，以及它们对炎症衰老（inflammaging）表型的潜在贡献仍未阐明。本研究整合单细胞与空间转录组学技术，系统解析衰老小鼠卵巢的细胞组成及细胞间信号传导网络的变化。本研究鉴定出随年龄增长而丰度显著升高的特定巨噬细胞与T细胞亚群，它们是老年卵巢中促炎信号的核心来源。此外，本研究预测这类促炎细胞与颗粒细胞群之间存在双向信号传导通路，该通路或可损伤卵泡的生长与发育，同时促进免疫细胞向卵巢组织的招募。上述发现为解析卵巢炎症衰老的驱动机制提供了全新的研究视角。本研究采用Slide-seq技术，对2月龄及约14月龄C57BL6/J雌性小鼠的全卵巢组织切片开展空间转录组学检测。