Genetic and epigenetic stability of human pluripotent stem cells

Key Points Recent studies that exploit novel high-resolution genome-wide approaches have reported frequent accumulation of genomic and epigenomic alterations in human pluripotent cells that can affect multiple properties and compromise their quality or use. Importantly, severe safety concerns arise when considering the use of these cells in regenerative therapies. On the basis of recent large-scale meta-analysis, the most recurrent genomic change in both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) is amplification of chromosome 12. Other commonly detected changes are at chromosomes 8, 12p, i(20)q10 and X. The most recurrent copy number variant (CNV) is amplification of at 20q11.21. Trisomy of chromosome 17, which is common in hESCs, has not been observed in hiPSCs. Instead, trisomy of chromosome 8 is detected more often in hiPSCs than in hESCs. On the basis of current knowledge, genomic stability of hiPSCs is not dependent of the method used for reprogramming. However, the reprogramming process has been reported to induce genomic and epigenetic changes. Importantly, early passages of hiPSCs can consist of mosaic populations of cells. The epigenome of hESCs is highly dynamic and sensitive to variation. Variation and instability in imprinting, X-chromosome inactivation and DNA methylation of developmental and cancer genes has been reported in different conditions. hiPSCs have been reported to be highly similar to hESCs for their epigenomic profiles. However, often hiPSCs may also show remnants of the epigenomic memory from somatic parent cells and sometimes activate abnormal pattern of genes or show higher methylation levels compared to the hESCs. Importantly, careful and frequent monitoring of the cells is required to ensure the genomic integrity of the cells, as unidentified aberrations may lead to distorted results and may raise safety issues for therapeutic use. Future integrative approaches exploiting genome-wide sequencing techniques will supplement and provide valuable and comprehensive information on the genomic and epigenomic integrity of pluripotent cells and their derivates. Human pluripotent stem cells hold promise for disease modelling and for cell-based regenerative medicine. This Review summarizes our growing understanding of the genetic and epigenetic abnormalities that can occur in these cells, including their phenotypic consequences and the safety implications for therapies. Studies using high-resolu