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Inhibition of pluripotent stem cell-derived teratoma formation by small molecules
Open accessAbstract
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…
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“Of greatest concern is the potential for highly proliferative uncommitted progenitors or residual hPSCs to be present in the final SC-islet product that have the potential to form tumors.158–160”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [160]
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Metadata
- Authors
- Lee, M.-O., Moon, S. H., Jeong, H.-C., Yi, J.-Y., Lee, T.-H., Shim, S. H., Rhee, Y.-H., Lee, S.-H., Oh, S.-J., Lee, M.-Y., Han, M.-J., Cho, Y. S., Chung, H.-M., Kim, K.-S., & Cha, H.-J.
- Affiliations
- Sogang University (KR)
- CHA University (KR)
- Sejong University (KR)
- Hanyang University (KR)
- Dongguk University (KR)
- Harvard University (US)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Konkuk University (KR)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-08-05
- Volume
- 110
- Issue
- 35
- Pages
- E3281-90
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3761568
- OpenAlex
- W2065594892
- Cited by
- 246
- References
- 68
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 18 · 2023: 15 · 2022: 16 · 2021: 21 · 2020: 19 · 2019: 22 · 2018: 16 · 2017: 21 · 2016: 32 · 2015: 24 · 2014: 20 · 2013: 5
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KRIBB Repository (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS070577, NS070577)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- teratoma prevention, human pluripotent stem cells, human embryonic stem cells, human induced pluripotent stem cells, small molecule inhibitors, survivin, BCL10, quercetin, YM155, selective cell death, apoptosis, p53, dopaminergic neurons, smooth muscle cells
- MeSH terms
- B-Cell CLL-Lymphoma 10 Protein, Survivin, Cell Differentiation, Cells, Cultured, Humans, Imidazoles, Mitochondria, Naphthoquinones, Teratoma, Tumor Suppressor Protein p53, Apoptosis, Gene Expression Profiling, Stem Cell Transplantation, Pluripotent Stem Cells, Adaptor Proteins, Signal Transducing, Inhibitor of Apoptosis Proteins, Small Molecule Libraries
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