CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice

Abstract

Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although many substances have been suggested to improve the rate of embryo implantation targeting enhancement of endometrial receptivity, currently there rarely are effective evidence-based treatments to prevent or cure this condition. Here we strongly suggest minimally-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention. Chemokine CXCL12 derived from pre- and peri-implanting embryos significantly enhances the rates of embryo attachment and promoted endothelial vessel formation and sprouting in vitro. Consistently, intra-uterine CXCL12 administration in C57BL/6 mice improved endometrial receptivity showing increased integrin β3 and its ligand osteopontin, and induced endometrial angiogenesis displaying increased numbers of vessel formation near the lining of endometrial epithelial layer with higher CD31 and CD34 expression. Furthermore, intra-uterine CXCL12 application dramatically promoted the rates of embryo implantation with no morphologically retarded embryos. Thus, our present study provides a novel evidence that improved uterine endometrial receptivity and enhanced angiogenesis induced by embryo-derived chemokine CXCL12 may aid to develop a minimally-invasive therapeutic strategy for clinical treatment or supplement for the patients with repeated implantation failure with less risk.

Transcriptomic analysis of mid‐secretory endometrium reveals essential immune factors associated with pregnancy after single euploid blastocyst transfer

“…Recently, intra-uterine administration of CXCL12 has been shown to improve endometrial receptivity and promote embryo implantation in mice. 29 Downregulation of DKK1 secreted by endometrial decidual cells decreases the trophoblast cell invasion. [30][31][32] Interestingly, our endometrial signatures were significantly enriched in immune and metabolic pathways.…”

“…For instance, both DEG analysis and weighted gene co‐expression network analysis identified the downregulation of CXCL12 and DKK1 in the non‐pregnant group. Recently, intra‐uterine administration of CXCL12 has been shown to improve endometrial receptivity and promote embryo implantation in mice 29 . Downregulation of DKK1 secreted by endometrial decidual cells decreases the trophoblast cell invasion 30–32 …”

Construction of circRNA‐miRNA‐mRNA network in the pathogenesis of recurrent implantation failure using integrated bioinformatics study

“…Noteworthy, Koo et al showed that pre‐ and peri‐implanting embryos‐derived CXCL12 and its connection with CXCR4 and CXCR7 increase the receptivity of the endometrium and promote angiogenesis. They also indicated that the intra‐uterine application of CXCL12 should be considered as a non‐invasive therapeutic option for treatment RIF patients 58 . PTGS2, which is also noticed as cyclooxygenase‐2 (COX‐2), is an essential enzyme in prostaglandins' biosynthesis.…”

Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models

“…Further, using the commercial system, we demonstrated that hUC-PRP is enriched with several factors that play important roles in the endometrium. Identified factors included: HGF, which has been related with proliferation ( Yoshida et al , 2004 ) and decidualization ( Zhang, 2010 ); PDGF-BB, which is largely involved in tissue contraction and migration of stromal cells ( Gargett and Masuda, 2010 ); EGF, which promotes endometrial growth ( Ejskjaer et al , 2005 ) and early pregnancy ( Large et al , 2014 ); and SDF-1α, which enhances endometrial receptivity ( Koo et al , 2021 ). Altogether, these factors show substantial potential for endometrial-specific regeneration and support the translation of hUC-PRP for clinical treatment of endometrial disorders, such as AS and EA.…”