In Vivo Tumorigenicity of the 20q11.21 Amplicon in an Engraftment Model of hPSCs and Differentiated Liver Cells.

Autor:	Pridgeon CS; MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, L69 3GE, UK., Forootan SS; MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, L69 3GE, UK., Zhang F; MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, L69 3GE, UK., Harper N; MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, L69 3GE, UK., Palmer D; Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK., Weightmann R; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK., Gregory S; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK., Hewitt Z; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK., Baker D; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK.; Sheffield Children's Hospital, Sheffield Diagnostic Genetic Services, Sheffield, S10 2TH, UK., Halliwell J; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK., Moore H; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK., Ricci E; Veterinary Pathology and Public Health, Institute of Veterinary Science, University of Liverpool, CH64 7TE, UK., Andrews PW; Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, UK., Poptani H; Centre for Pre-clinical Imaging, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, L69 3BX, UK., Hay DC; MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, UK., Park BK; MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, L69 3GE, UK., Goldring CEP; MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, L69 3GE, UK.
Jazyk:	angličtina
Zdroj:	Journal of stem cells & regenerative medicine [J Stem Cells Regen Med] 2023 Apr 30; Vol. 19 (1), pp. 3-13. Date of Electronic Publication: 2023 Apr 30 (Print Publication: 2023).
DOI:	10.46582/jsrm.1901002
Abstrakt:	Human pluripotent stem cells (hPSCs) are a promising source of somatic cells for clinical applications and disease modelling. However, during culture they accumulate genetic aberrations such as amplification of 20q11.21 which occurs in approximately 20% of extensively cultured hPSC lines and confers a BCL2L1-mediated survival advantage. During the production of the large number of cells required for transplantation and therapy these aberrations may become unavoidable which has important safety implications for therapies and may also impact upon disease modelling. Presently, these risks are poorly understood; whilst it is apparent that large-scale genetic aberrations can pose an oncogenic risk, the risks associated with smaller, more insidious changes have not been fully explored. In this report, the effects of engraftment of human embryonic stem cells (hESCs) and hESC-derived hepatocyte-like cells (HLCs) with and without amplification of the 20q11.21 minimal amplicon and isochromosome 20q (i20q) in SCID-beige mice are presented. The cells were tracked in vivo using a luminescent reporter over a period of approximately four months. Intrasplenic injection of hESCs showed greater engraftment potential and the formation of more severely disruptive lesions in the liver and spleen of animals injected with cells containing 20q11.21 compared with i20q and wild type. HLCs with 20q11.21 engrafted more successfully and formed more severely disruptive lesions than wild type cells or cells with i20q. These results reinforce the notion that karyotyping of therapeutic hPSC is required for transplant, and suggest that screening for known common aberrations is necessary. Further work to identify commonly arising genetic aberrations should be performed and routine screening for hPSCs intended for therapeutic use should be used. Competing Interests: This work was funded by UK Regenerative Medicine PlatformThe authors declare no conflicts of interest. (Copyright © Journal of Stem Cells and Regenerative Medicine.)
Databáze:	MEDLINE
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