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Increased risk of genetic and epigenetic instability in human embryonic stem cells associated with specific culture conditions

PloS one, 2015-02, Vol.10 (2), p.e0118307 [Peer Reviewed Journal]

COPYRIGHT 2015 Public Library of Science ;COPYRIGHT 2015 Public Library of Science ;2015 Garitaonandia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;2015 Garitaonandia et al 2015 Garitaonandia et al ;ISSN: 1932-6203 ;EISSN: 1932-6203 ;DOI: 10.1371/journal.pone.0118307 ;PMID: 25714340

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Title:
Increased risk of genetic and epigenetic instability in human embryonic stem cells associated with specific culture conditions
Author: Garitaonandia, Ibon ; Amir, Hadar ; Boscolo, Francesca Sesillo ; Wambua, Gerald K ; Schultheisz, Heather L ; Sabatini, Karen ; Morey, Robert ; Waltz, Shannon ; Wang, Yu-Chieh ; Tran, Ha ; Leonardo, Trevor R ; Nazor, Kristopher ; Slavin, Ileana ; Lynch, Candace ; Li, Yingchun ; Coleman, Ronald ; Gallego Romero, Irene ; Altun, Gulsah ; Reynolds, David ; Dalton, Stephen ; Parast, Mana ; Loring, Jeanne F ; Laurent, Louise C
Roh, Tae-Young
Subjects: Algorithms ; Biochemistry ; Bioinformatics ; Cell culture ; Cell Culture Techniques ; Cell Differentiation ; Cell Line ; Cell proliferation ; Cell Self Renewal ; Cell Transformation, Neoplastic - genetics ; Cells, Cultured ; Chief executive officers ; Chromosome Aberrations ; Chromosome Deletion ; Chromosome Duplication ; Chromosomes, Human, Pair 12 ; Chromosomes, Human, Pair 17 ; Chromosomes, Human, Pair 20 ; Combinatorial analysis ; Deoxyribonucleic acid ; Differentiation (biology) ; DNA ; DNA Methylation ; Drug development ; Embryo cells ; Embryo fibroblasts ; Embryonic stem cells ; Embryos ; Enzymes ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Gene expression ; Gene Expression Profiling ; Genome, Human ; Genomes ; Genomic Instability ; Health sciences ; Human Embryonic Stem Cells - cytology ; Human Embryonic Stem Cells - metabolism ; Human Embryonic Stem Cells - pathology ; Humans ; Mechanical properties ; Medicine ; Methylation ; Molecular biology ; Mutation ; Oct-4 protein ; p53 Protein ; Phenotype ; Physiology ; Pluripotency ; Pluripotent Stem Cells - metabolism ; Polymorphism, Single Nucleotide ; Reproductive health ; RNA ; Stability ; Stem cell transplantation ; Stem cells ; Substrates ; Time Factors ; Transplantation ; Tumor proteins ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - genetics
Is Part Of: PloS one, 2015-02, Vol.10 (2), p.e0118307
Description: The self-renewal and differentiation capacities of human pluripotent stem cells (hPSCs) make them a promising source of material for cell transplantation therapy, drug development, and studies of cellular differentiation and development. However, the large numbers of cells necessary for many of these applications require extensive expansion of hPSC cultures, a process that has been associated with genetic and epigenetic alterations. We have performed a combinatorial study on both hESCs and hiPSCs to compare the effects of enzymatic vs. mechanical passaging, and feeder-free vs. mouse embryonic fibroblast feeder substrate, on the genetic and epigenetic stability and the phenotypic characteristics of hPSCs. In extensive experiments involving over 100 continuous passages, we observed that both enzymatic passaging and feeder-free culture were associated with genetic instability, higher rates of cell proliferation, and persistence of OCT4/POU5F1-positive cells in teratomas, with enzymatic passaging having the stronger effect. In all combinations of culture conditions except for mechanical passaging on feeder layers, we noted recurrent deletions in the genomic region containing the tumor suppressor gene TP53, which was associated with decreased mRNA expression of TP53, as well as alterations in the expression of several downstream genes consistent with a decrease in the activity of the TP53 pathway. Among the hESC cultures, we also observed culture-associated variations in global gene expression and DNA methylation. The effects of enzymatic passaging and feeder-free conditions were also observed in hiPSC cultures. Our results highlight the need for careful assessment of the effects of culture conditions on cells intended for clinical therapies.
Publisher: United States: Public Library of Science
Language: English
Identifier: ISSN: 1932-6203
EISSN: 1932-6203
DOI: 10.1371/journal.pone.0118307
PMID: 25714340
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central
Public Library of Science (PLoS)
ProQuest Central
DOAJ Directory of Open Access Journals

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Increased risk of genetic and epigenetic instability in human embryonic stem cells associated with specific culture conditions

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