ATP mediates the interaction between human blastocyst and endometrium

Abstract

Objective Embryo implantation needs a reciprocal interaction between competent embryo and receptive endometrium. Adenosine triphosphate (ATP) produced by stressed or injured cells acts as an important signalling molecule. This study aims to investigate whether adenosine triphosphate (ATP) plays an important role in the dialogue of human blastocyst‐endometrium. Materials and methods The concentration of lactate was analysed in culture medium from human embryos collected from in vitro fertilization patients. Extracellular ATP was measured by ATP Bioluminescent Assay Kit. Ishikawa cells and T‐HESCs were treated with ATP, ATP receptor antagonist, ATP hydrolysis enzyme or inhibitors of ATP metabolic enzymes. The levels of gene expression were evaluated by real‐time PCR and immunoassay. Results We showed that injured human endometrial epithelial cells could rapidly release ATP into the extracellular environment as an important signalling molecule. In addition, blastocyst‐derived lactate induces the release of non‐lytic ATP from human endometrial receptive epithelial cells via connexins. Extracellular ATP stimulates the secretion of IL8 from epithelial cells to promote the process of in vitro decidualization. Extracellular ATP could also directly promote the decidualization of human endometrial stromal cells via P2Y‐purinoceptors. More importantly, the supernatants of injured epithelial cells clearly induce the decidualization of stromal cells in time‐dependent manner. Conclusion Our results suggest that ATP should play an important role in human blastocyst‐endometrium dialogue for the initiation of decidualization.

Exometabolomic analysis of decidualizing human endometrial stromal and perivascular cells

“…66–68 Furthermore, ATP has been shown to promote IL-8 secretion in endometrial epithelial cells and stimulate decidualization. 69 Thus, redirecting hypoxanthine towards the upstream purines may represent a mechanism to heighten decidualization of PVC cells. Taken together, the data suggest that a balance and switch between ATP, a mainly proinflammatory molecule, and adenosine, an anti-inflammatory factor, is required for an effective decidual response.…”

Single cell proteomics profiling reveals that embryo-secreted TNF-α plays a critical role during embryo implantation to the endometrium

“…Second, increased secretion may be harmful to the endometrium. Other potential mechanisms also contribute to the secretion of TNF-α, such as a recent study which demonstrated that ATP is involved in the secretion of TNF-α from the membrane [8,21]. Third, the downstream target of TNF-α warrants further clari cation.…”

“…Embryonic factors are also critical for proper embryo implantation process during in vitro culture in IVF. For example, it is well-known that embryos secrete a wide variety of proteins and other factors to guide successful implantation in the endometrium [8]. Although cytokines have been extensively studied and long used as biomarkers in many settings including for preterm labor and preeclampsia [9], the quantitative analysis of cytokines in embryo culture medium has always been a challenge due to low volume, low concentration, and possible contamination from exosomes and microvesicles in the medium itself.…”

Single Cell Proteomics Profiling Revealing that Embryo Secreted TNF-α play Critical Role during Embryo Implantation to Endometrium

“…For example, recent study has shown that ATP is involved in the secretion of TNF-α from membrane. 8,22 Thirdly, the down-stream target of TNFα warrant further clari cation. Secretion of excessive TNF-α increased the expression of pyroptosis marker, Caspase-8, which may indicate the possibility that excessive TNF-α leads to the pyroptosis of the embryo and endometrium, leading to the demise of the embryo during implantation window.…”

“…For example, it has been well known that embryo can secret different kinds of protein and nucleotides to pave the way for the successful invasion. 8 Although cytokines have been long studied and used as biomarker in different diseases condition, including in preterm labor and preeclampsia, 9 the analysis of the cytokines in embryo culture medium has always been a challenge since it has few volume, low concentration, and it may be secreted with other forms such as exosome and micro-vesicle, therefore it increase the di culty for quantitative detection. Recent advance in single molecule, micro uidic analysis has improved the detection to more sensitive level.…”