News

Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells.

Mol Neurobiol. 2019 Jun;56(6):4346-4363. doi: 10.1007/s12035-018-1368-2. Epub 2018 Oct 13.

Augustyniak J1, Lenart J2, Gaj P3, Kolanowska M4, Jazdzewski K3,4, Stepien PP5,6,7, Buzanska L8.

Author information

1 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

2 Department of Neurochemistry, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

3 Laboratory of Human Cancer Genetics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.

4 Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.

5 Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.

6 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

7 Centre of New Technologies, University of Warsaw, Warsaw, Poland.

8 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

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.

KEYWORDS:

Bezafibrate; Mitochondrial biogenesis; NSC; PGC-1α; PPAR’s; hiPSC

 

Additional information