Valproic Acid Enhances iPSC Induction From Human Bone Marrow-Derived Cells Through the Suppression of Reprogramming-Induced Senescence

Abstract

Reprogramming of human somatic cells into pluripotent cells (iPSCs) by defined transcription factors is an extremely inefficient process. Treatment with the histone deacetylase inhibitor valproic acid (VPA) during reprogramming can improve the induction of iPSCs. To examine the specific mechanism underlying the role of VPA in reprogramming, we transfected human bone marrow-derived cells (HSC-J2 and HSC-L1) with lentiviruses carrying defined factors (OCT4, SOX2, KLF4, and c-MYC, OSKM) in the presence of VPA. We found that, OSKM lentiviruses caused significant senescence in transfected cells. Administration of VPA, however, significantly suppressed this reprogramming-induced stress. Notably, VPA treatment improved cell proliferation in the early stages of reprogramming, and this was related to the down-regulation of the activated p16/p21 pathway. In addition, VPA also released the G2/M phase blockade in lentivirus-transfected cells. This study demonstrates a new mechanistic role of the histone deacetylase inhibitor in enhancing the induction of pluripotency. J. Cell. Physiol. 231: 1719-1727, 2016. © 2015 Wiley Periodicals, Inc.

Mitochondrial DNA Hypomethylation Is a Biomarker Associated with Induced Senescence in Human Fetal Heart Mesenchymal Stem Cells

“…We then used PCR to quantitate senescence-related genes that have been previously reported [38, 39, 50]. We found that the caveolin-1 gene (CAV1) was upregulated in senescent MSCs (Figure 2(c)), although we did not detect a significant change in APO-J and OX1.…”

“…Cellular senescence was quantitated by measuring the activity of SA- β -Gal as previously described [38, 39]. MSCs were collected and fixed using 3% formaldehyde for 3–5 min at room temperature.…”

Metabolic Reprogramming, Autophagy, and Reactive Oxygen Species Are Necessary for Primordial Germ Cell Reprogramming into Pluripotency

“…HDAC inhibitors have been widely used in the field of cell reprogramming, since their addition to culture increases the efficiency. Specifically, VPA has been shown to display this mentioned improvement in the arising of iPSCs, even making Klf4 and cMyc dispensable from the reprogramming cocktail [51], by reducing senescence of reprogrammed cells [52]. However, CBP -specific knockout in PGCs did not alter their histone acetylation levels [53], suggesting that histone acetylation in PGCs is dependent on other histone acetylases different than CBP.…”

Profiling the long noncoding RNA interaction network in the regulatory elements of target genes by chromatin in situ reverse transcription sequencing

“…Mouse fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) by Pou5f1-Sox2-Klf4-Myc (OSKM) cocktail factors (Chen et al 2012(Chen et al , 2016Zhang et al 2013;Zhai et al 2015). Briefly, the OSKM lentiviruses were packaged in 293T cells by cotransfecting the lenti-OSKM with viral packaging vectors using Lipofectamine 2000 (Invitrogen).…”