title: Immunologic and chemical targeting of the tight-junction protein Claudin-6 eliminates tumorigenic human pluripotent stem cells.
abstract: The tumorigenicity of human pluripotent stem cells is a major safety concern for their application in regenerative medicine. Here we identify the tight-junction protein Claudin-6 as a cell-surface-specific marker of human pluripotent stem cells that can be used to selectively remove Claudin-6-positive cells from mixed cultures. We show that Claudin-6 is absent in adult tissues but highly expressed in undifferentiated cells, where it is dispensable for human pluripotent stem cell survival and self-renewal. We use three different strategies to remove Claudin-6-positive cells from mixed cell populations: an antibody against Claudin-6; a cytotoxin-conjugated antibody that selectively targets undifferentiated cells; and Clostridium perfringens enterotoxin, a toxin that binds several Claudins, including Claudin-6, and efficiently kills undifferentiated cells, thus eliminating the tumorigenic potential of human pluripotent stem cell-containing cultures. This work provides a proof of concept for the use of Claudin-6 to eliminate residual undifferentiated human pluripotent stem cells from culture, highlighting a strategy that may increase the safety of human pluripotent stem cell-based cell therapies.
authors.affiliation: Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Ben-David
authors.forename: Neta
authors.initials: N
authors.lastname: Nudel
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057167:Claudins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004768:Enterotoxins / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D062725:Tight Junction Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D057167:Claudins; D004768:Enterotoxins; D062725:Tight Junction Proteins; C035598:enterotoxin, Clostridium; C122101:claudin 6