You are hereJune 12, 2016 | ESCs/iPSCs
Correlation of Age and Mitochondrial Mutations in iPSCs
Review of “Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs” from Cell Stem Cell by Stuart P. Atkinson
The use of induced pluripotent stem cell (iPSC) based regenerative therapies are likely to be relevant to the rising aged population across the globe. However, increased age correlates to an increases DNA damage and genomic instability [1, 2] and a new study from the laboratories of Taosheng Huang and Shoukhrat Mitalipov now reports that hiPSCs from older patient samples present with a much higher accumulation of mtDNA mutations than younger patient samples . Furthermore, they find that these mutations can affect iPSC metabolic function. Does this represent an important barrier to the clinical application of these utile cells?
The authors first assessed skin fibroblasts from iPSCs from elderly patients using Illumina MiSeq-based mtDNA sequencing. Extensive analysis suggested that unique somatic mtDNA mutations can randomly arise in individual skin fibroblasts and screens may not detect all mutations present. However, iPSCs generated from such cells can give rise to homoplasmic mutations (100%) or highly heteroplasmic mutations (80%) which may lead to mitochondrial dysfunction.
But is this the same in other cell types used to generate iPSCs? Similar analyses in peripheral blood mononuclear cells (continuously regenerated from stem cell pool with a shorter lifespan) found that blood iPSC lines also display unique mtDNA mutations not detected in whole blood, and so the accumulation of mutations in individual cells appears to be a common phenomenon in elderly donors.
Looking back in time at younger (24 years) donor skin fibroblasts, the studies analysis suggested that while the range of mutations detected was similar in young and old primary fibroblasts and iPSCs, mtDNA abnormalities gradually accumulate with aging and could adversely affect iPSC quality. Furthermore, while the appearance of some mutations in patient fibroblasts and while blood suggests a common progenitor or germline origin, most mtDNA mutations in adults appear to be of somatic origin.
Finally, the study sought to discover the functional consequences of mutations, by differentiating iPSC lines into fibroblasts and assessing their oxidative metabolism profile. Many of the mutations found were non-synonymous or resided in RNA coding genes, so it was no surprise when the study found that both homoplasmic or high heteroplasmic mtDNA mutations and the accumulation of low heteroplasmic mutations led to reduced metabolic function, which may contribute to the aging process .
In summary, this detailed study suggests a higher level of scrutiny of mtDNA mutation and iPSC metabolic profiles, especially for older patients. Further highlighting a need for an increase in the level of care is the finding of a much higher mutation frequency in adult iPSCs mtDNA (this study) compared to nuclear genome abnormalities .
- Garinis GA, van der Horst GT, Vijg J, et al. DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol 2008;10:1241-1247.
- Lombard DB, Chua KF, Mostoslavsky R, et al. DNA repair, genome stability, and aging. Cell 2005;120:497-512.
- Kang E, Wang X, Tippner-Hedges R, et al. Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs. Cell Stem Cell 2016;18:625-636.
- Schon EA, DiMauro S, and Hirano M Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 2012;13:878-890.
- Johannesson B, Sagi I, Gore A, et al. Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors. Cell Stem Cell 2014;15:634-642.