Abstract
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.
Highlights
The pregnancy rate of women declines with age
We found C-X-C motif chemokine ligand 5 (CXCL5), an inflammatory cytokine expressed in multiple types of cells, as a gene encoding for a senescence-associated secretory phenotype (SASP) factor in aging embryos
Based on comprehensive gene expression analysis, we identified CXCL5 as an aging-associated gene in early human embryos and found that CXCL5 treatment led to quality decline of young mouse embryos, resulting in implantation failure
Summary
The pregnancy rate of women declines with age. Women who are over 38 years of age showed a sharp decline in their pregnancy potential (Tan et al, 1992). Senescence-associated secretory phenotype (SASP) describes secretion of multiple pro-inflammatory cytokines, chemokines, growth factors, and extracellular proteases by senescent cells (Coppe, Desprez, Krtolica, & Campisi, 2010) These factors act on cells of origin or neighboring cells through autocrine/paracrine mechanisms (Acosta et al, 2008). It was reported that expression levels of C-C motif chemokine ligand 5 (Ccl5), one of the SASP factor, was increased in theca-interstitial cells of aging ovary, resulting in promotion of granulosa cell apoptosis (Shen et al, 2019) This change was associated with the attenuation of preantral follicle growth, survival and estrogen secretion as well as inhibition of oocyte maturation. We demonstrated that the implantation rates of embryos were affected by regulating CXCL5 signaling mediated by its cognate receptor CXCR2 in murine embryos
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