Cyclophilin A plays an important role in embryo implantation through activating Stat3

in Reproduction

Correspondence should be addressed to H-L Diao or X-H Zhang; Email: hldiao1976@hotmail.com or zhangxiuhong@ahmu.edu.cn

*(T Yu and S Lin are equally contributed to this work)

Restricted access

Embryo implantation is a crucial step for the successful establishment of mammalian pregnancy. Cyclophilin A (CYPA) is a ubiquitously expressed intracellular protein and is secreted in response to inflammatory stimuli to regulate diverse cellular functions. However, there are currently no reports about the role of CYPA in embryo implantation. Here, we examine the expression pattern of CYPA during mouse early pregnancy and explore the potential role of CYPA during implantation. CYPA is expressed in the subluminal stroma surrounding the implanting blastocyst on day 5 of pregnancy, but not at inter-implantation sites. In ovariectomized mice, estrogen and progesterone significantly stimulate CYPA expression. When pregnant mice are injected intraperitoneally with CYPA inhibitor, the numbers of implantation sites are significantly reduced. Using an in vitro stromal cell culture system, Ppia siRNA knockdown of CYPA and CYPA-specific inhibitor treatment partially inhibits levels of CD147, MMP3 and MMP9. Decreased CYPA expression also significantly inhibits Stat3 activity and expands estrogen responsiveness. Taken together, CYPA may play an important role during mouse embryo implantation.

Supplementary Materials

    • Figure S1 Identification of the purity of cultured stromal cells. Vimentin and CK18 were used to assess the purification of the uterine stromal cells collected from pregnant day 4 mice. mESC, mouse endometrial stromal cells collected from pregnant day 4 mice; Uterus, uterine tissue collected from pregnant day 4 mice.
    • Figure S2 Blastocysts recovered from the mice uterus which were treated with DMSO and TMN355 on day 3, 4 of pregnancy.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 436 436 436
Full Text Views 17 17 17
PDF Downloads 11 11 11
  • AchacheHRevelA 2006 Endometrial receptivity markers, the journey to successful embryo implantation. Human Reproduction Update 12 731746. (https://doi.org/10.1093/humupd/dml004)

    • Search Google Scholar
    • Export Citation
  • AlexanderCMHansellEJBehrendtsenOFlanneryMLKishnaniNSHawkesSPWerbZ 1996 Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development 122 17231736.

    • Search Google Scholar
    • Export Citation
  • AplinJDMeseguerMSimonCOrtizMECroxattoHJonesCJ 2001 Muc1, glycans and the cell-surface barrier to embryo implantation. Biochemistry Society Transactions 29 153156. (https://doi.org/10.1042/bst0290153)

    • Search Google Scholar
    • Export Citation
  • BanyBMHarveyMBSchultzGA 2000 Expression of matrix metalloproteinases 2 and 9 in the mouse uterus during implantation and oil-induced decidualization. Journal of Reproduction and Fertility 120 125134. (https://doi.org/10.1530/reprod/120.1.125)

    • Search Google Scholar
    • Export Citation
  • ChenLBeltonRJJrNowakRA 2009a Basigin-mediated gene expression changes in mouse uterine stromal cells during implantation. Endocrinology 150 966976. (https://doi.org/10.1210/en.2008-0571)

    • Search Google Scholar
    • Export Citation
  • ChenLXSunBCZhangSWHeYJLiXRHeZJ 2009b The mechanisms of microenvironments influence on vasculogenic mimicry between intraocular and subcutaneous melanoma. Zhonghua Yan Ke Za Zhi 45 641646. (https://doi.org/10.3760/cma.j.issn.0412-4081.2009.07.013)

    • Search Google Scholar
    • Export Citation
  • DaikokuTMatsumotoHGuptaRADasSKGassmannMDuboisRNDeySK 2003 Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is regulated in a cell-specific and ovarian steroid hormone-dependent manner. Evidence for differential function of HIFs during early pregnancy. Journal of Biological Chemistry 278 76837691. (https://doi.org/10.1074/jbc.M211390200)

    • Search Google Scholar
    • Export Citation
  • DasSKYanoSWangJEdwardsDRNagaseHDeySK 1997 Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period. Developmental Genetics 21 4454. (https://doi.org/10.1002/(SICI)1520-6408(1997)21:1<44::AID-DVG5>3.0.CO;2-8)

    • Search Google Scholar
    • Export Citation
  • DekelNGnainskyYGranotIRacicotKMORG 2014 The role of inflammation for a successful implantation. American Journal of Reproductive Immunology 72 141147. (https://doi.org/10.1111/aji.12266)

    • Search Google Scholar
    • Export Citation
  • FengWXinYXiaoYLiWSunD 2015 Cyclophilin A enhances cell proliferation and xenografted tumor growth of early gastric cancer. Digestive Diseases and Sciences 60 27002711. (https://doi.org/10.1007/s10620-015-3694-9)

    • Search Google Scholar
    • Export Citation
  • FischerGWIttmann-LieboldBLangKKiefhaberTSchmidFX 1989 Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337 476478. (https://doi.org/10.1038/337476a0)

    • Search Google Scholar
    • Export Citation
  • HandschumacherREHardingMWRiceJDruggeRJSpeicherDW 1984 Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226 544547. (https://doi.org/10.1126/science.6238408)

    • Search Google Scholar
    • Export Citation
  • IgakuraTKadomatsuKKanameTMuramatsuHFanQWMiyauchiToyama YKunoNYuasaSTakahashiM 1998 A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis. Developmental Biology 194 152165. (https://doi.org/10.1006/dbio.1997.8819)

    • Search Google Scholar
    • Export Citation
  • JinZGMelaragnoMGLiaoDFYanCHaendelerJSuhYALambethJDBerkBC 2000 Cyclophilin A is a secreted growth factor induced by oxidative stress. Circulation Research 87 789796. (https://doi.org/10.1161/01.res.87.9.789)

    • Search Google Scholar
    • Export Citation
  • KunoNKadomatsuKFanQWHagiharaMSendaTMizutaniSMuramatsuT 1998 Female sterility in mice lacking the basigin gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily. FEBS Letters 425 191194. (https://doi.org/10.1016/s0014-5793(98)00213-0)

    • Search Google Scholar
    • Export Citation
  • LiQKannanADemayoFJLydonJPCookePSYamagishiHSrivastavaDBagchiMKBagchiIC 2011 The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331 912916. (https://doi.org/10.1126/science.1197454)

    • Search Google Scholar
    • Export Citation
  • LinSZhuYYHuWYangYLuoJMHuSJYangZM 2018 Decidual expression and regulation of fatty acid desaturase 3 during mouse decidualization. Reproduction 156 429437. (https://doi.org/10.1530/REP-18-0145)

    • Search Google Scholar
    • Export Citation
  • NigroEScudieroOSarnataroDMazzarellaGSofiaMBiancoADanieleA 2013 Adiponectin affects lung epithelial A549 cell viability counteracting TNFalpha and IL-1ss toxicity through AdipoR1. International Journal of Biochemical and Cell Biology 45 11451153. (https://doi.org/10.1016/j.biocel.2013.03.003)

    • Search Google Scholar
    • Export Citation
  • NorwitzERSchustDJFisherSJ 2001 Implantation and the survival of early pregnancy. New England Journal of Medicine 345 14001408. (https://doi.org/10.1056/NEJMra000763)

    • Search Google Scholar
    • Export Citation
  • SatohKMatobaTSuzukiJO’DellMRNigroPCuiZMohanAPanSLiLJinZG 2008 Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation. Circulation 117 30883098. (https://doi.org/10.1161/circulationaha.107.756106)

    • Search Google Scholar
    • Export Citation
  • SherryBYarlettNStruppACeramiA 1992 Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages. PNAS 89 35113515. (https://doi.org/10.1073/pnas.89.8.3511)

    • Search Google Scholar
    • Export Citation
  • SunXBartosAWhitsettJADeySK 2013 Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Molecular Endocrinology 27 14921501. (https://doi.org/10.1210/me.2013-1086)

    • Search Google Scholar
    • Export Citation
  • XiaoLJChangHDingNZNiHKadomatsuKYangZM 2002 Basigin expression and hormonal regulation in mouse uterus during the peri-implantation period. Molecular Reproduction and Development 63 4754. (https://doi.org/10.1002/mrd.10128)

    • Search Google Scholar
    • Export Citation
  • ZhangSLinHKongSWangSWangHWangHArmantDR 2013 Physiological and molecular determinants of embryo implantation. Molecular Aspects of Medicine 34 939980. (https://doi.org/10.1016/j.mam.2012.12.011)

    • Search Google Scholar
    • Export Citation
  • ZhaoYCChiYJYuYSLiuJLSuRWMaXHShanCHYangZM 2008 Polyamines are essential in embryo implantation: expression and function of polyamine-related genes in mouse uterus during peri-implantation period. Endocrinology 149 23252332. (https://doi.org/10.1210/en.2007-1420)

    • Search Google Scholar
    • Export Citation
  • ZhuDWangZZhaoJJCalimeriTMengJHideshimaTFulcinitiMKangYFicarroSBTaiYT 2015 The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells. Nature Medicine 21 572580. (https://doi.org/10.1038/nm.3867)

    • Search Google Scholar
    • Export Citation