title: Inhibition of pluripotent stem cell-derived teratoma formation by small molecules.
abstract: The future of safe cell-based therapy rests on overcoming teratoma/tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC-derived cells. Taken together, these results provide the "proof of concept" that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.
authors.affiliation: Department of Life Sciences, College of Natural Sciences, Sogang University, Seoul 121-742, Korea.
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Lee
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Moon
authors.forename: Ho-Chang
authors.initials: HC
authors.lastname: Jeong
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Yi
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Lee
authors.forename: Sung Han
authors.initials: SH
authors.lastname: Shim
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Seok-Jeong
authors.initials: SJ
authors.lastname: Oh
authors.forename: Moo-Yeol
authors.initials: MY
authors.lastname: Lee
authors.forename: Min-Joon
authors.initials: MJ
authors.lastname: Han
authors.forename: Yee Sook
authors.initials: YS
authors.lastname: Cho
authors.forename: Hyung-Min
authors.initials: HM
authors.lastname: Chung
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D017209:Apoptosis; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002454:Cell Differentiation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D054852:Small Molecule Libraries; D033581:Stem Cell Transplantation; D000077022:Survivin; D013724:Teratoma / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D054852:Small Molecule Libraries; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C523798:sepantronium
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