The presence of blastocyst within the uteri facilitates lumenal epithelium transformation for implantation via upregulating lysosome proteostasis activity
The presence of blastocyst within the uteri facilitates lumenal epithelium transformation for implantation via upregulating lysosome proteostasis activity
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DOI：
10.1080/15548627.2023.2247747
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发表时间：
2023-08-24
期刊：
影响因子：
13.3
通讯作者：
Wang，Haibin
中科院分区：
文献类型：
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作者：
Wang，Peike;Du，Shuailin;Wang，Haibin
哺乳动物子宫内膜被腔上皮（Le）覆盖，腔上皮（Le）直接与胚泡相互作用，并且在植入期间胚胎和接受性子宫之间的相互串扰的建立中起重要作用。然而，在接受性窗口期囊胚对子宫分化的影响还远未得到很好的理解。通过激光捕获显微切割（LCM）分离的子宫Le的转录组学分析，证实了无胚胎假孕小鼠和有胚胎妊娠小鼠之间Le发生了全局基因表达变化。一些差异表达的基因，包括上调的Areg（双调蛋白）、Ihh（印度刺猬）、Lifr（白血病抑制因子受体）和下调的Msx 1（msh同源框1）、Pgr（孕酮受体）和Gata 2（加塔结合蛋白2），已被报道调节子宫容受性的建立。此外，我们还发现囊胚诱导溶酶体数量和酸化的增加，这与子宫Le中溶酶体水解酶活性的增强一致。进一步的研究发现，胚泡来源的IGF 2参与激活上皮细胞STAT 3以诱导溶酶体水解酶表达，并且抑制溶酶体功能使子宫受体标记基因表达和胚胎植入脱轨。最后，基于上皮细胞和分离的溶酶体的蛋白质组学数据，揭示了CLDN 1（claudin 1）和MUC 1（mucin 1，跨膜），两种众所周知的成功植入的下调分子，被上皮溶酶体降解。缩写ACTB：肌动蛋白β; AREG：双调蛋白; ATP 6 V0 A4：ATP酶，H+转运，溶酶体V0亚基A4; Baf A1：巴弗洛霉素A1; BSA：牛血清白蛋白; CLDN 1：claudin 1; CTSB：组织蛋白酶B; DEG：差异表达基因; E2：17β-雌二醇;电子自旋共振：雌激素受体; GATA 2：加塔结合蛋白2; GLA：半乳糖苷酶，α;- 你好基因本体论; HBEGF：肝素结合EGF样生长因子; IGF 1 R：胰岛素样生长因子1受体; Ihh：印度刺猬; ISH：原位杂交; LAMP 1：溶酶体相关膜蛋白1; LCM：激光捕获显微切割; Le：腔上皮; LGMN：豆荚蛋白; LIF：白血病抑制因子; LIFR：LIF受体α; MSX 1：msh同源框1; MUC 1：粘蛋白1，跨膜; P4：孕酮; PBS：磷酸盐缓冲盐水; PCA：主成分分析; PPT 1：棕榈酰蛋白硫酯酶1; PGR：黄体酮受体; PSP：假孕; PTGS 2/COX 2：前列腺素内过氧化物合酶2; qPCR：定量实时聚合酶链反应; SP：妊娠; TFEB：转录因子EB。
The mammalian endometrium is covered by the lumenal epithelium (Le), which directly interacts with the blastocyst and plays an important role in the establishment of reciprocal crosstalk between the embryo and receptive uterus during implantation. However, the effect of the blastocyst on uterine differentiation during the window of receptivity is far from well understood. Through transcriptomic profiling of the uterine Le isolated by laser capture microdissection (LCM), it was demonstrated that global gene expression changes occurred in Le between pseudopregnant mice without embryos and pregnant mice with embryos. Some differentially expressed genes, including upregulatedAreg(amphiregulin),Ihh(Indian hedgehog),Lifr(leukemia inhibitory factor receptor) and downregulatedMsx1(msh homeobox 1),Pgr(progesterone receptor), andGata2(GATA binding protein 2) in pregnant mice, have been reported to regulate the establishment of uterine receptivity. Besides, we found that blastocysts induced an increase in both the number and acidification of lysosome, consistent with enhanced lysosomal hydrolase activity in uterine Le. Further exploration uncovered that blastocyst-derived IGF2 was involved into the activation of epithelial STAT3 to induce lysosomal hydrolase expression, and inhibition of lysosomal function derails both uterine receptive maker gene expressions and embryo implantation. Finally, based on the proteomic data of both epithelia and the separated lysosome, it was revealed that CLDN1 (claudin 1) and MUC1 (mucin 1, transmembrane), two well-known downregulated molecules for successful implantation, are degraded by epithelial lysosome. In brief, our data demonstrated that blastocysts induced normal epithelium differentiation with lysosome activation to promote the uterine epithelial differentiation for embryo implantation.AbbreviationsACTB: actin beta; AREG: amphiregulin; ATP6V0A4: ATPase, H+transporting, lysosomal V0 subunit A4; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CLDN1: claudin 1; CTSB: cathepsin B; DEGs: differentially expressed genes; E2: 17β-estradiol; ESR: estrogen receptor; GATA2: GATA binding protein 2; GLA: galactosidase, alpha; GO: gene ontology; HBEGF: heparin-binding EGF-like growth factor; IGF1R: insulin-like growth factor 1 receptor; Ihh: Indian hedgehog; ISH: in situ hybridization; LAMP1: lysosomal-associated membrane protein 1; LCM: laser capture microdissection; Le: lumenal epithelium; LGMN: legumain; LIF: leukemia inhibitory factor; LIFR: LIF receptor alpha; MSX1: msh homeobox 1; MUC1: mucin 1, transmembrane; P4: progesterone; PBS: phosphate-buffered saline; PCA: principal component analysis; PPT1: palmitoyl-protein thioesterase 1; PGR: progesterone receptor; PSP: pseudopregnancy; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; qPCR: quantitative real-time polymerase chain reaction; SP: pregnancy; TFEB: transcription factor EB.