Abstract
Bezafibrate (BZ) regulates mitochondrial biogenesis by activation of PPAR’s receptors and enhancing the level of PGC-1α coactivator. In this report, we investigated the effect of BZ on the expression of genes (1) that are linked to different pathways involved in mitochondrial biogenesis, e.g., regulated by PPAR’s receptors or PGC-1α coactivator, and (2) involved in neuronal or astroglial fate, during neural differentiation of hiPSC. The tested cell populations included hiPSC-derived neural stem cells (NSC), early neural progenitors (eNP), and neural progenitors (NP). RNA-seq analysis showed the expression of PPARA, PPARD receptors and excluded PPARG in all tested populations. The expression of PPARGC1A encoding PGC-1α was dependent on the stage of differentiation: NSC, eNP, and NP differed significantly as compared to hiPSC. In addition, BZ-evoked upregulation of PPARGC1A, GFAP, S100B, and DCX genes coexist with downregulation of MAP2 gene only at the eNP stage of differentiation. In the second task, we investigated the cell sensitivity and mitochondrial biogenesis upon BZ treatment. BZ influenced the cell viability, ROS level, mitochondrial membrane potential, and total cell number in concentration- and stage of differentiation-dependent manner. Induction of mitochondrial biogenesis evoked by BZ determined by the changes in the level of SDHA and COX-1 protein, and mtDNA copy number, as well as the expression of NRF1, PPARGC1A, and TFAM genes, was detected only at NP stage for all tested markers. Thus, developmental stage-specific sensitivity to BZ of neurally differentiating hiPSC can be linked to mitochondrial biogenesis, while fate commitment decisions to PGC-1α (encoded by PPARGC1A) pathway.
Highlights
The fibrate groups of drugs, derivatives of dehydrocholic acid, are clinically used in the treatment of lipid disorders [1, 2]
We aimed to answer the question whether upregulation of mitochondrial biogenesis by BZ in Human-induced pluripotent stem cells (hiPSC) can be related to the regulation of their neural fate commitment
Our results indicated that upregulation of mitochondrial biogenesis and sensitivity to BZ of hiPSC is dependent upon the stage of neural development, while fate commitment decisions are linked to PGC-1α pathway
Summary
The fibrate groups of drugs, derivatives of dehydrocholic acid, are clinically used in the treatment of lipid disorders [1, 2]. Bezafibrate (BZ) was used in this study due to its identified influence on mitochondrial biogenesis [4]; information on the effect of BZ on the process of neural cell differentiation is very scarce, only a few publications describing the influence of this group of compounds on the nervous system [5]. The effects of BZ are mediated by the activation of PPAR receptors that regulate the expression of genes involved in lipid homeostasis and energy metabolism and many other processes, including inflammation, cellular differentiation, and proliferation [2]. PAR-peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) encoded by PPARGC1A gene is considered the major regulator of mitochondrial biogenesis, playing a role in the regulation of expression of antioxidant defenses [6,7,8]. Upon the initiation of differentiation, a switch from glycolysis to oxidative phosphorylation occurs in the differentiating cells because the more specialized cells have a greater demand for ATP. mtDNA copy number seems to be an important factor for the appropriate initiation of differentiation
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