title: A Synthetic Hybrid Molecule for the Selective Removal of Human Pluripotent Stem Cells from Cell Mixtures.
abstract: A major hurdle in stem cell therapy is the tumorigenic risk of residual undifferentiated stem cells. This report describes the design and evaluation of synthetic hybrid molecules that efficiently reduce the number of human induced pluripotent stem cells (hiPSCs) in cell mixtures. The design takes advantage of Kyoto probe 1 (KP-1), a fluorescent chemical probe for hiPSCs, and clinically used anticancer drugs. Among the KP-1-drug conjugates we synthesized, we found an exceptionally selective, chemically tractable molecule that induced the death of hiPSCs. Mechanistic analysis suggested that the high selectivity originates from the synergistic combination of transporter-mediated efflux and the cytotoxicity mode of action. The present study offers a chemical and mechanistic rationale for designing selective, safe, and simple reagents for the preparation of non-tumorigenic clinical samples.
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Di
authors.initials: D
authors.lastname: Mao
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Ando
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Sato
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Hirata
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Katsuda
authors.affiliation: Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Eihachiro
authors.initials: E
authors.lastname: Kawase
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Ting-Fang
authors.initials: TF
authors.lastname: Kuo
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8501, Japan.
authors.forename: Itsunari
authors.initials: I
authors.lastname: Minami
authors.affiliation: Institute for Biomedical Sciences and Department of Cardiovascular Medicine, School of Medicine, Shinshu University, Matsumoto, 390-8621, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiba
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Institute for Frontier Medical Sciences and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nakatsuji
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002469:Cell Separation / Q000379:methods*; D005456:Fluorescent Dyes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012235:Rhodamines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; C000597746:Kyoto probe 1; D012235:Rhodamines
keywords: ABC transporters; cytotoxicity; drug conjugates; fluorescent probes; stem cell therapy