Vitamin C Enhances Nanog Expression Via Activation of the JAK/STAT Signaling Pathway

Abstract

Vitamin C (Vc), also known as ascorbic acid, is involved in many important metabolic and physiological reactions in the body. Here, we report that Vc enhances the expression of Nanog and inhibits retinoic acid-induced differentiation of embryonic stem cells. We investigated Vc regulation of Nanog through Janus kinase/signal transducer and activator of transcription pathway using cell signaling pathway profiling systems, and further confirmed by specific pathway inhibition. Using overexpression and knockdown strategies, we demonstrated that STAT2 is a new positive regulator of Nanog and is activated by phosphorylation following Vc treatment. In addition, site mutation analysis identified that STAT2 physically occupies the Nanog promoter, which was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Taken together, our data suggest a role for Vc in Nanog regulation networks and reveal a novel role for STAT2 in regulating Nanog expression. STEM CELLS 2014;32:166-176

In vitro and in vivo assessment of high-dose vitamin C against murine tumors

“…Low-dose vitamin C (25-50 µg/ml) does not induce apoptosis; conversely, it is associated with stem cell proliferation and maintenance (4,8). Previous studies have shown that high-dose vitamin C (10 g/day) is effective at treating cancer (12).…”

“…Recently, evidence has emerged to suggest that vitamin C has additional functions other than its anti-oxidant ability. Vitamin C activates the Jak-Stat2 signaling pathway and enhances Nanog expression (4), which has been demonstrated to be a direct target of TLR4 (5) and is associated with stem cell properties (6,7). Vitamin C induces the generation of induced pluripotent stem cells (iPSCs) (8) and the transition from pre-iPSCs to iPSCs (9).…”

“…Vitamin C induces the generation of induced pluripotent stem cells (iPSCs) (8) and the transition from pre-iPSCs to iPSCs (9). Vitamin C also inhibits the retinoid acid-induced differentiation of mouse embryonic stem cells (4).…”

Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

“…In vitro studies with J1ES cells, a cell model used to evaluate radial glial cell differentiation, indicate that both AA and SVCT2 are key regulators in maintaining the radial phenotype. They also may regulate the pluripotency of neural stem cells, as AA induces the expression of the pluripotency gene, Nanog, through activation of the JAK/STAT signaling pathway and inhibition of retinoic acid-dependent neuronal differentiation [21,22].…”

Efeito da Laserfototerapia associada ou não à Vitamina C na indução de membranas celulares (cell sheets) de células-tronco da polpa dentária humana

“…Tendo em vista a complexidade dos processos e reações do ciclo celular influenciadas por VC, alguns autores sugerem que outras intervenções, além da supressão dos radicais livres, poderiam somar-se e justificar a eficiência dessa vitamina. Assim, em estudos mais atuais, foram reconhecidas: 1) sua ação sobre o aumento da expressão de Nanog através da ativação da via de sinalização JAK / STAT (Wu et al, 2014); 2) repressão da expressão dos genes p53 (Shi et al, 2010) e TET1 , agindo no processo de senescência celular e auxiliando na reprogramação de células somáticas em IPSs; 3) aumento da atividade da enzina telomerase em PDLSCs; onde 4) também induziu a formação de Cell Sheets através do aumento do metabolismo celular e, consequentemente, da produção e deposição de MEC (Wei et al, 2012).…”