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Human embryonic stem cells commonly display large mitochondrial DNA deletions
Journal Contribution - Journal Article
Mitochondria play an important role in early embryogenesis and contribute to the unique biology of stem cells. Undifferentiated human and mouse embryonic stem cells (ESCs) contain relatively few spherical and immature mitochondria, similar to those in human and other mammalian preimplantation embryos. The number and maturity of mitochondria increases upon differentiation, concurrent with the switch from glycolysis to oxidative phosphorylation (OXPHOS) for energy production. Conversely, human somatic mitochondria undergo morphological and functional changes during reprogramming to induced pluripotent stem cells (iPSCs), with a shift from OXPHOS to glycolysis. Furthermore, attenuating mitochondrial function in undifferentiated human ESCs increases the mRNA levels of the pluripotency genes NANOG, POU5F1 (OCT4) and SOX2, compromises the cells' differentiation potential and increases the number of persisting tumorigenic cells after differentiation.
Despite an increasing number of reports on the high instability of the nuclear genome of hESCs and the clear role of mitochondria in maintaining the pluripotent state, the integrity of the mitochondrial genome has received little attention. A 2005 study showed that two out of nine hESC lines investigated had acquired heteroplasmic point mutations during culture. A more recent report found by deep sequencing that four human iPSC lines harbored a large number of mitochondrial DNA (mtDNA) point mutations, both hetero- and homoplasmic, but detected no evidence of large insertions or deletions.
We screened for mtDNA deletions in 16 hESC lines, at one to six different passages ranging from passage 3 to 334.
All tested hESC lines carry a plethora of diverse mtDNA deletions, frequently very large, at an average mutation load of 23%. The number and type of mutations do not seem to correlate with time in culture and can be detected at the earliest passages studied. These deletions do not appear to affect the differentiation potential of the cells, and are still present in terminally differentiated cells. Whether such mutations have any implications for therapeutic applications of hESCs remains to be determined.
Despite an increasing number of reports on the high instability of the nuclear genome of hESCs and the clear role of mitochondria in maintaining the pluripotent state, the integrity of the mitochondrial genome has received little attention. A 2005 study showed that two out of nine hESC lines investigated had acquired heteroplasmic point mutations during culture. A more recent report found by deep sequencing that four human iPSC lines harbored a large number of mitochondrial DNA (mtDNA) point mutations, both hetero- and homoplasmic, but detected no evidence of large insertions or deletions.
We screened for mtDNA deletions in 16 hESC lines, at one to six different passages ranging from passage 3 to 334.
All tested hESC lines carry a plethora of diverse mtDNA deletions, frequently very large, at an average mutation load of 23%. The number and type of mutations do not seem to correlate with time in culture and can be detected at the earliest passages studied. These deletions do not appear to affect the differentiation potential of the cells, and are still present in terminally differentiated cells. Whether such mutations have any implications for therapeutic applications of hESCs remains to be determined.
Journal: Nat Biotechnol
ISSN: 1087-0156
Issue: January
Volume: 31
Pages: 20-23
Publication year:2013
Keywords:human embryonic stem cells, mitochondria, mitochondrial DNA