Inhibition of Protein Kinase C Signaling Maintains Rat Embryonic Stem Cell Pluripotency

• Published in: The Journal of biological chemistry Vol. 288; no. 34; pp. 24351 - 24362
• Main Authors: Rajendran, Ganeshkumar, Dutta, Debasree, Hong, James, Paul, Arindam, Saha, Biswarup, Mahato, Biraj, Ray, Soma, Home, Pratik, Ganguly, Avishek, Weiss, Mark L., Paul, Soumen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.08.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Biology; Chromatin Modification; Embryonic Stem Cell; Embryonic Stem Cells - cytology; Embryonic Stem Cells - enzymology; Indoles - pharmacology; Maleimides - pharmacology; MicroRNAs - metabolism; NF-kappa B - metabolism; NF-κB; PKC; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - enzymology; Protein Kinase C-epsilon - antagonists & inhibitors; Protein Kinase C-epsilon - metabolism; Protein Kinase Inhibitors - pharmacology; Rat; Rats; Signal Transduction - drug effects; Signal Transduction - physiology; Chromatin Modification; NF-κB; PKC; Rat; Embryonic Stem Cell
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.455725

Embryonic stem cell (ESC) pluripotency is orchestrated by distinct signaling pathways that are often targeted to maintain ESC self-renewal or their differentiation to other lineages. We showed earlier that inhibition of PKC signaling maintains pluripotency in mouse ESCs. Therefore, in this study, we investigated the importance of protein kinase C signaling in the context of rat ESC (rESC) pluripotency. Here we show that inhibition of PKC signaling is an efficient strategy to establish and maintain pluripotent rESCs and to facilitate reprogramming of rat embryonic fibroblasts to rat induced pluripotent stem cells. The complete developmental potential of rESCs was confirmed with viable chimeras and germ line transmission. Our molecular analyses indicated that inhibition of a PKCζ-NF-κB-microRNA-21/microRNA-29 regulatory axis contributes to the maintenance of rESC self-renewal. In addition, PKC inhibition maintains ESC-specific epigenetic modifications at the chromatin domains of pluripotency genes and, thereby, maintains their expression. Our results indicate a conserved function of PKC signaling in balancing self-renewal versus differentiation of both mouse and rat ESCs and indicate that targeting PKC signaling might be an efficient strategy to establish ESCs from other mammalian species. Background: Signaling mechanisms regulating rat embryonic stem cell (rESC) pluripotency are understood poorly. Results: Inhibition of PKC signaling promotes rESC self-renewal without compromising developmental potency. Conclusion: PKC signaling contributes to the balance of self-renewal versus differentiation of rESCs. Significance: PKC signaling could be targeted to derive rat pluripotent stem cells to establish transgenic models and for regenerative studies.