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Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells.
Mol Neurobiol. 2019 Jun; 56(6):4346-4363.MN

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.

Authors+Show Affiliations

Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.Department of Neurochemistry, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.Laboratory of Human Cancer Genetics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.Laboratory of Human Cancer Genetics, Centre of New Technologies, University of Warsaw, Warsaw, Poland. Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. Centre of New Technologies, University of Warsaw, Warsaw, Poland.Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland. buzanska@imdik.pan.pl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30315479

Citation

Augustyniak, Justyna, et al. "Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells." Molecular Neurobiology, vol. 56, no. 6, 2019, pp. 4346-4363.
Augustyniak J, Lenart J, Gaj P, et al. Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells. Mol Neurobiol. 2019;56(6):4346-4363.
Augustyniak, J., Lenart, J., Gaj, P., Kolanowska, M., Jazdzewski, K., Stepien, P. P., & Buzanska, L. (2019). Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells. Molecular Neurobiology, 56(6), 4346-4363. https://doi.org/10.1007/s12035-018-1368-2
Augustyniak J, et al. Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells. Mol Neurobiol. 2019;56(6):4346-4363. PubMed PMID: 30315479.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells. AU - Augustyniak,Justyna, AU - Lenart,Jacek, AU - Gaj,Paweł, AU - Kolanowska,Monika, AU - Jazdzewski,Krystian, AU - Stepien,Piotr Pawel, AU - Buzanska,Leonora, Y1 - 2018/10/13/ PY - 2018/04/27/received PY - 2018/09/27/accepted PY - 2018/10/14/pubmed PY - 2019/8/30/medline PY - 2018/10/14/entrez KW - Bezafibrate KW - Mitochondrial biogenesis KW - NSC KW - PGC-1α KW - PPAR’s KW - hiPSC SP - 4346 EP - 4363 JF - Molecular neurobiology JO - Mol. Neurobiol. VL - 56 IS - 6 N2 - 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. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/30315479/Bezafibrate_Upregulates_Mitochondrial_Biogenesis_and_Influence_Neural_Differentiation_of_Human_Induced_Pluripotent_Stem_Cells_ L2 - https://dx.doi.org/10.1007/s12035-018-1368-2 DB - PRIME DP - Unbound Medicine ER -