title: Uterine selection of human embryos at implantation.
abstract: Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca(2+) signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca(2+) fluxes whereas low-quality embryos caused a heightened and prolonged Ca(2+) response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation.
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Jan J
authors: JJ
authors: Brosens
authors: 1] Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK [2] Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W12 ONN, UK.
authors: Madhuri S
authors: MS
authors: Salker
authors: Department for Reproductive Medicine and Gynecology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
authors: Gijs
authors: G
authors: Teklenburg
authors: Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W12 ONN, UK.
authors: Jaya
authors: J
authors: Nautiyal
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Scarlett
authors: S
authors: Salter
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Emma S
authors: ES
authors: Lucas
authors: Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W12 ONN, UK.
authors: Jennifer H
authors: JH
authors: Steel
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Mark
authors: M
authors: Christian
authors: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
authors: Yi-Wah
authors: YW
authors: Chan
authors: Department for Reproductive Medicine and Gynecology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
authors: Carolien M
authors: CM
authors: Boomsma
authors: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
authors: Jonathan D
authors: JD
authors: Moore
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Geraldine M
authors: GM
authors: Hartshorne
authors: Department of Physiology and Immunology, Medical School, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
authors: Sandra
authors: S
authors: Sućurović
authors: Department of Physiology and Immunology, Medical School, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
authors: Biserka
authors: B
authors: Mulac-Jericevic
authors: Department for Reproductive Medicine and Gynecology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
authors: Cobi J
authors: CJ
authors: Heijnen
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Siobhan
authors: S
authors: Quenby
authors: Molecular Cancer Research, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
authors: Marian J Groot
authors: MJ
authors: Koerkamp
authors: Molecular Cancer Research, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
authors: Frank C P
authors: FC
authors: Holstege
authors: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX, UK.
authors: Anatoly
authors: A
authors: Shmygol
authors: 1] Department for Reproductive Medicine and Gynecology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands [2] Division of Developmental Origins of Adult Diseases (DOHaD), University of Southampton, Coxford Road, Southampton SO16 5YA, UK.
authors: Nick S
authors: NS
authors: Macklon
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000196:embryology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003656:Decidua / Q000166:cytology*; D010064:Embryo Implantation / Q000502:physiology*; D004622:Embryo, Mammalian / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D050883:HSC70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011388:Prolactin / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014357:Trypsin / Q000378:metabolism; D014599:Uterus / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D034741:RNA, Small Interfering; D011388:Prolactin; D014357:Trypsin