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    • tropisetron In contrast to previously pub http

    2018-11-08

    In contrast to previously published data (Folmes et al., 2013; Menendez et al., 2011) we found that protein complexes involved in oxidative phosphorylation (OXPHOS), such as ATP synthase, NADH dehydrogenase (Complex I), Cytochrome b-c1, Cytochrome C, Cytochrome b5, H+-transporting two-sector ATPase, as well as mTOR signaling (54 molecules involved in total) were up-regulated in both hiPSCs (Supplementary Table 7). At the same time, among the markers of the transition to glycolytic metabolism we found only four up-regulated proteins: ENO2, TKT, ALDOB and PGAM1. Therefore, observations made for our hiPSC lines did not agree with previously described reprogramming-associated induction of glycolysis and down-regulation of mitochondrial reserve capacity and ATP turnover (Folmes et al., 2013; Menendez et al., 2011). This could be due to several factors, including differences between data obtained on the early (right after reprogramming) (Folmes et al., 2013; Menendez et al., 2011) and late passages of hiPSC, as well as between hiPSCs of different somatic origins. Importantly, it has been recently demonstrated that although the energy production of hiPSC favors glycolysis over OXPHOS, mitochondria in hiPSC still possess functional respiratory complexes (Zhang et al., 2011). The decoupling of glycolysis from OXPHOS was suggested to be regulated by several factors, including mitochondrial uncoupling protein 2 (UCP2) (Zhang et al., 2011). In addition, there are studies confirming that mitochondrial dynamics and maintenance of proper mitochondrial network integrity are crucial for the maintenance of pluripotency (Xu et al., 2013). Nevertheless, pivotal lipogenic enzymes acetyl-CoA carboxylase (ACACA) and fatty tropisetron synthase (FASN) (involved in lipogenic switch) were up-regulated in our study in both hiPSCs, in line with a recent publication (Vazquez-Martin et al., 2013). Variations on the level of genomic DNA between different pluripotent stem cells, as well as transcriptional and epigenetic profile differences can contribute to their pluripotency, stability and differentiation potential (Bock et al., 2011; Sugawara et al., 2012; Ma et al., 2014). Recent genome-wide analysis of genetically matched sets of hiPSC, hESC, and somatic cell nuclear transfer (NT) ESC has revealed that both NT-ESC and hiPSC contained a number of de novo copy variations; exome sequencing has demonstrated that hiPSC carry, on average, six non-synonymous point mutations per line (Ma et al., 2014). In addition, hiPSC retained residual DNA methylation patterns typical of parental cells (Ma et al., 2014). On the other hand, proteomic studies have shown that hiPSC proteome is almost indistinguishable from that of hESC (Munoz et al., 2011; Phanstiel et al., 2011; Kim et al., 2012). From about 2500 proteins confidently quantified in two different studies only 58 and 293 proteins were differentially expressed between hiPSC and hESC in 2 fold or less (Munoz et al., 2011; Phanstiel et al., 2011). Moreover, when the data sets from these two studies were compared, only three proteins were found to be consistently up-regulated in hESC vs. hiPSC: CRABP1, AK3 and SLC2A1 (Benevento and Munoz, 2012). Therefore, minor genomic variations or epigenetic profiles difference between different hiPSC/hESC lines may not be observed in the global proteome comparison. In our study, quantitative comparison of each hiPSC with hESC revealed only ~50–150 proteins up- or down-regulated in both hiPSCs compared to H9 cells. CRABP1 and AK3 were also down-regulated in hiPSCs vs hESC (Supplementary Tables 3 and 4). Different proteins within the same functional network were either up- or down-regulated in hiPSCs compared to hESC, and no coordinated changes were found within any network. However, it is of interest that energy production was up-regulated in both hiPSCs vs. hESC. There were a number of canonical pathways (p-value<0.00001) up-regulated in both hiPSCs in comparison to H9 cells, such as EIF2 signaling, regulation of eIF4 and p70S6K signaling and mTOR.