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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Highly proliferative uncommitted progenitors or residual hPSCs in the final SC-islet product have the potential to form tumors.
“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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“The survival of undifferentiated pluripotent stem cells is highly dependent on anti-apoptotic factors, such as survivin [46,47], and overexpression of survivin in embryonic stem cells, pluripotent cells and somatic stem cells [48,49], as well as the correlation between higher BIRC5 expression and lower cell differenti…”
BackgroundCho, S.-J., Kim, S.-Y., Jeong, H.-C., Cheong, H., Kim, D., Park, S.-J., Choi, J.-J., Kim, H., Chung, H., Moon, S., et al. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.10.004 · Cited by 29 · see citing works
Self-citationMovahed, A. Y., Bagheri, R., Savatier, P., Šarić, T., & Moradi, S. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102543 · Cited by 28 · see citing works
Induced Pluripotent Stem Cells for Ischemic Stroke Treatment
Duan, R., Gao, Y., He, R., Jing, L.-J., Li, Y.-F., Gong, Z., Yao, Y.-B., Luan, T., Zhang, C.-P., Li, L., et al. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.628663 · Cited by 28 · see citing works
‘Off-the-shelf’ immunotherapy with iPSC-derived rejuvenated cytotoxic T lymphocytes
Ando, M., & Nakauchi, H. (2016) · Experimental Hematology · doi:10.1016/j.exphem.2016.10.009 · Cited by 38 · see citing works
Plasma-activated medium selectively eliminates undifferentiated human induced pluripotent stem cells
Matsumoto, R., Shimizu, K., Nagashima, T., Tanaka, H., Mizuno, M., Kikkawa, F., Hori, M., & Honda, H. (2016) · Regenerative Therapy · doi:10.1016/j.reth.2016.07.001 · Cited by 28 · see citing works
Han, J.-J., Qian, X.-M., Wu, Q., Jha, R., Duan, J.-S., Yang, Z., Maher, K., Nie, S., & Xu, C. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.07.033 · Cited by 27 · see citing works
Okawa, H., Kayashima, H., Sasaki, J., Miura, J., Kamano, Y., Kosaka, Y., Imazato, S., Yatani, H., Matsumoto, T., & Egusa, H. (2016) · Stem Cells International · doi:10.1155/2016/6240794 · Cited by 27 · see citing works
“Irradiation of osteogenically induced iPSCs prior to transplantation [54], introduction of a suicide gene into the pluripotency locus [55], or co-treatment with small molecules such as quercetin and YM155 [56] may be useful strategies to prevent tumorigenesis after implantation.”
Miyagawa, S., Fukushima, S., Imanishi, Y., Kawamura, T., Mochizuki‐Oda, N., Masuda, S., & Sawa, Y. (2016) · Current Gene Therapy · doi:10.2174/1566523216666160119094143 · Cited by 29 · see citing works
“It is important that cell viability and functionality were maintained even if cells that differentiated from hPSCs were treated with survivin inhibitors [54].”
BackgroundInfluentialRegenerative Medicine for the Heart: Perspectives on Stem-Cell Therapy
Cho, G.-S., Fernandez, L., & Kwon, C. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6063 · Cited by 31 · see citing works
“The inhibitors did not seem to affect the survival and function of differentiated cell types, such as dopamine neurons and smooth muscle cells (73).”
Functional Cardiomyocytes Derived from Isl1 Cardiac Progenitors via Bmp4 Stimulation
Cagavi, E., Bartulos, O., Suh, C., Sun, B., Yue, Z.-C., Jiang, Z., Yue, L.-X., & Qyang, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110752 · Cited by 26
“or iPSCs in differentiated cultures [42, 43].”
Selective elimination of human pluripotent stem cells by a marine natural product derivative.
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Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies
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Effect of small molecules on cell reprogramming
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“Studies have used iPSC-specific antiapoptotic factors, such as survivin or Bcl10, with smallmolecule inhibitors to eliminate pluripotent cells with teratoma potential [36].”
BackgroundLiver organoids: Current advances and future applications for hepatology
Kim, Y., Kang, M., Mamo, M. G., Adisasmita, M., Huch, M., & Choi, D. (2025) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.1040 · Cited by 26 · see citing works
Clinical‐scale purification of pluripotent stem cell derivatives for cell‐based therapies
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“used a similar strategy to identify the expression signatures of pro- and anti-apoptotic genes to reduce the tumor formation potential of hPSC-derived populations [32].”
BackgroundMethodFrom tissue engineering to engineering tissues: the role and application of in vitro models.
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Elimination of undifferentiated human embryonic stem cells by cardiac glycosides
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“One example of chemical methods is the use of survivin inhibitor YM155, which can induce apoptotic cell death of hPSCs without damaging the functionality of differentiated cells.(137) For antibody-based methods, Choo et al.”
MethodKim, K.-T., Park, J.-C., Jang, H., Lee, H., Park, S., Kim, J., Kwon, O., Go, Y.-H., Jin, Y., Kim, W., et al. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120295 · Cited by 26 · see citing works
Self-citationCha, B.-H., Kim, J.-S., Bello, A., Lee, G.-H., Kim, D., Kim, B., Arai, Y., Choi, B., Park, H., & Lee, S.-H. (2020) · Advancement of science · doi:10.1002/advs.202001365 · Cited by 22
Self-citationUsing Gene Editing to Establish a Safeguard System for Pluripotent Stem-Cell-Based Therapies
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In situ label-free quantification of human pluripotent stem cells with electrochemical potential.
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“Recently, quercetin was reported to be used in the selective removal of undifferentiated human pluripotent stem cells after transplantation (41).”
BackgroundGenomic instability, driver genes and cell selection: Projections from cancer to stem cells
Ben‐David, U. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.08.005 · Cited by 23 · see citing works
- 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
- Health Sciences › Medicine › Genetics › 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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