Metabolism Is a Key Regulator of Induced Pluripotent Stem Cell Reprogramming

Figure 1

Metabolic differences between embryonic stem cells (ESC) (a) and induced pluripotent stem cells (iPSC) (b). Glycolytic rate, glucose consumption, and lactate production are altered in iPSC by both the retention of somatic cell metabolic memory and the acquisition of aberrant metabolic characteristics [87, 88]. Significantly, due to the retention of metabolic memory or the acquisition of metabolic aberrations, the capacity for iPSC to modulate glycolysis in response to changes in oxygen (O₂) is impaired. In contrast, this oxygen response, whereby glucose to lactate flux is significantly increased under physiological (5%) oxygen conditions relative to that under atmospheric (20%) oxygen, is well characterised in both ESC [28, 29] and the blastocyst [105]. Levels of polyunsaturated fatty acids (PUFAs), including arachidonic acid, linoleic acid, docosapentaenoic acid, and adrenic acid, are lower in iPSC than in ESC [7]. PUFAs regulate oxidative metabolism by undergoing beta-oxidation to produce acetyl-CoA and can be converted to eicosanoids, which can mitigate oxidative stress, caused by reactive oxygen species (ROS) as a result of oxidative phosphorylation (OxPhos), through the activation of peroxisome proliferator-activated receptor gamma (PPARγ) [100, 101]. Eicosanoids also plausibly regulate mitochondrial biogenesis and function though the action of PPARγ recruiting PPARγ coactivator 1-α (PGC-1α) [102]. Levels of the methyl donor and cofactor S-adenosyl methionine (SAM) are higher in iPSC than in ESC [7], resulting in a greater methylation (me) of histones in iPSC through the action of histone methyltransferases (HMT). SAM is produced from methionine (Met) and, when demethylated, results in S-adenosyl-L-homocysteine (SAH) which is hydrolysed to homocysteine (HCY) and converted into methionine. Mitochondria in iPSC morphologically resemble both those of ESC and somatic cells [9]. Mitochondrial activity in iPSC is affected by the culture conditions under which they are reprogrammed, whereby iPSC derived under physiological oxygen possess mitochondria that are less active and more ESC-like when compared to those of iPSC derived under atmospheric oxygen [88]. It has also been shown that iPSC acquire and accumulate mitochondrial DNA (mtDNA) mutations [90], with the frequency of these mutations increasing with parental somatic cell age [93]; however, the degree to which these mutations impact mitochondrial metabolism and activity in iPSC is unknown. However, in somatic cells, mtDNA mutations can contribute not only to mitochondrial dysfunction [95] but also to cellular senescence and telomere shortening [96]. Thick arrows indicate increased flux/activity. Red arrows indicate pathways affected by the retention of somatic cell memory or acquisition of metabolic aberrations in iPSC.

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