Sperm-carried IGF2: towards the discovery of a spark contributing to embryo growth and development

Spermatozoa have been shown to carry key RNAs which, according to animal evidence, seem to play a role in early embryo development. In this context, a potential key growth regulator is insulin-like growth factor 2 (IGF2), a highly conserved paternally expressed imprinted gene involved in cell growth and proliferation which, recent observations indicate, is expressed in human spermatozoa. We herein hypothesized that sperm IGF2 gene expression and transmission at fertilization is required to support early embryo development. To test this hypothesis, we analyzed sperm IGF2 mRNA levels in the same semen aliquot used for homologous assisted reproductive technique (ART) in infertile couples and correlated these levels with embryo morphokinetics. To find a mechanistic explanation for the observed results, the transcriptomes of blastocysts obtained after injection of Igf2 mRNA in mouse parthenotes were analyzed. Sperm IGF2 mRNA negatively correlated with time of 2-cell stage (t2), t3, t4, t5, and time of expanded blastocyst (tEB), independently of maternal age, body mass index, anti-Müllerian hormone levels, and oocyte quality. An IGF2 mRNA index >4.9 predicted the ability of the embryos to reach the blastocyst stage on Day 5, with a sensitivity of 100% and a specificity of 71.6% (AUC 0.845; P < 0.001). In the animal study, transcriptome analysis demonstrated that 65 and 36 genes were, respectively, up- and down-regulated in the experimental group compared to the control group. These genes belong to pathways that regulate early embryo development, thus supporting the findings found in humans. This study has the potential to challenge the longstanding tenet that spermatozoa are simply vehicles carrying paternal DNA. Instead, it suggests that IGF2 mRNA in healthy spermatozoa provides critical support for early embryo development. Pre-ART sperm-carried IGF2 mRNA levels may be used as a marker to predict the chances of obtaining blastocysts to be transferred for infertile couples undergoing ART.