CXCL5‐CXCR2 signaling is a senescence‐associated secretory phenotype in preimplantation embryos

Pregnancy rate of women decreases with age due to declining quality of oocytes and embryos. However, there is no established method to improve pregnancy rate in aging women. In this study, we identified a senescence‐associated secretory phenotype (SASP) factor partially responsible for the decline in embryo implantation potential. Based on microarray analysis using young and aging human embryos at the same morphological grade, 702 genes showed >fivefold increases in aging human blastocysts. Among these genes, C‐X‐C motif chemokine 5 (CXCL5) showed 7.7‐fold increases in aging human blastocysts. However, no‐age‐dependent changes in expression of the CXCR2, the cognate receptor for CXCL5, were found. In aging mice, Cxcl5 transcript levels were also increased in oocytes and embryos. Treatment of young mouse embryos with CXCL5 decreased implantation rates, together with increased expression of aging markers (P53, P21, Pai‐1, and Il‐6). Moreover, CXCL5 treatment suppressed trophoblast outgrowth in young mouse blastocysts. Conversely, suppression of CXCL5‐CXCR2 signaling in aging mouse embryos using neutralizing antibodies and a receptor antagonist improved the implantation rate, leading to increases in pregnancy and delivery of normal pups. The gene expression pattern of these embryos was comparable to that in young mouse embryos showing enriched cell proliferation‐related pathways. In conclusion, we identified CXCL5 as a SASP factor in human and mouse embryos and suppression of CXCL5‐CXCR2 signaling during embryo culture improved pregnancy success in aging mice. Future analysis on CXCL5‐CXCR2 signaling suppression in human embryos could be the basis to improve embryo development and pregnancy outcome in middle‐aged infertile patients. We identified CXCL5 as a senescence‐associated secretory phenotype (SASP) factors in preimplantation embryos, showing elevated expression in embryos of older women and mice. The implantation rate of CXCL5‐treated young embryos from mice was decreased due to suppression of trophoblast cell proliferation. In aging embryos, suppression of CXCL5‐CXCR2 signaling during embryo culture might improve pregnancy outcome for middle‐aged women undergoing IVF.