title: Evidence for bystander signalling between human trophoblast cells and human embryonic stem cells.
abstract: Maternal exposure during pregnancy to toxins can occasionally lead to miscarriage and malformation. It is currently thought that toxins pass through the placental barrier, albeit bi-layered in the first trimester, and damage the fetus directly, albeit at low concentration. Here we examined the responses of human embryonic stem (hES) cells in tissue culture to two metals at low concentration. We compared direct exposures with indirect exposures across a bi-layered model of the placenta cell barrier. Direct exposure caused increased DNA damage without apoptosis or a loss of cell number but with some evidence of altered differentiation. Indirect exposure caused increased DNA damage and apoptosis but without loss of pluripotency. This was not caused by metal ions passing through the barrier. Instead the hES cells responded to signalling molecules (including TNF-α) secreted by the barrier cells. This mechanism was dependent on connexin 43 mediated intercellular 'bystander signalling' both within and between the trophoblast barrier and the hES colonies. These results highlight key differences between direct and indirect exposure of hES cells across a trophoblast barrier to metal toxins. It offers a theoretical possibility that an indirectly mediated toxicity of hES cells might have biological relevance to fetal development.
authors.affiliation: Musculoskeletal Research Unit, School of Clinical Sciences (North Bristol), University of Bristol, Bristol BS10 5NB.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Jones
authors.affiliation: Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gokhale
authors.affiliation: Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Allison
authors.affiliation: GMO 02 Medical Oncology Block, Medical Oncology, Charing Cross Campus, London SW7 2AZ.
authors.forename: Barry
authors.initials: B
authors.lastname: Sampson
authors.affiliation: Department of Obstetrics, Southmead Hospital, Bristol BS10 5NB.
authors.forename: Sharan
authors.initials: S
authors.lastname: Athwal
authors.affiliation: Department of Obstetrics, Southmead Hospital, Bristol BS10 5NB.
authors.forename: Simon
authors.initials: S
authors.lastname: Grant
authors.affiliation: Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrews
authors.affiliation: Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Allen
authors.affiliation: Musculoskeletal Research Unit, School of Clinical Sciences (North Bristol), University of Bristol, Bristol BS10 5NB.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Case
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002450:Cell Communication; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019216:Metals, Heavy / Q000633:toxicity; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018031:Connexin 43; D016207:Cytokines; D019216:Metals, Heavy; D014409:Tumor Necrosis Factor-alpha