Mature iPSCs and Mitochondrial Mutations

In 2006, the amazing discovery of induced pluripotent stem cells (iPSCs) (1) opened the floodgates to personalized regenerative medicine. Ophthalmology certainly joined the ensuing tidal wave of research, and the ability to produce donor-matched ocular cells – not to mention the option of reprogramming iPSCs derived from these cells – have peppered publications in the years since, with the research showing no signs of slowing down (2).

But every rose has its thorn, as recent work from Shoukhrat Mitalipov’s team demonstrates (3). They have shown that as people age, they accumulate somatic mutations in their mitochondrial DNA (mtDNA), which can then be carried into iPSC lines. In a panel of subjects aged between 24 and 72 years, iPSCs generated from younger donors had significantly fewer mtDNA mutations compared with those generated from elderly donors.

While it isn’t a new idea that mutations in mtDNA accumulate with age (4), this is the first clear evidence confirming the hypothesis. So what does this mean for iPSCs? Usually undetectable in the parental tissue – a proverbial needle in a genetic haystack – mtDNA mutations can become prominent in iPSC populations, which are cloned from individual donor cells. These mtDNA mutations may compromise cell function and respiration, thereby interfering with the therapeutic potential of iPSCs. Mitalipov and his colleagues demonstrated that metabolic function (as measured by respiratory chain complex activity and oxygen consumption rate) was indeed diminished in iPSCs harboring specific mtDNA mutations, compared with mutation-free controls. Confirming that the therapeutic benefits of iPSCs may be limited when the integrity of mtDNA is compromised. They also demonstrated that when mutated mtDNA was replaced with mitochondria obtained from the donor oocytes – a technique known as somatic cell nuclear transfer (SCNT) for which Mitalipov was a pioneer – normal metabolic function was restored.

Mitalipov noted, “it is imperative to produce and screen multiple iPSC lines for chromosomal, nuclear gene, and mtDNA defects, and to identify optimal tissues for iPSC induction.” This would likely mean producing and screening multiple iPSC lines per patient to allow selection of the line with the fewest mutations – and thus the greatest therapeutic potential.