Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells

Abstract

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. However, the low efficiency and slow kinetics of the reprogramming process have hampered progress with this technology. Here we report that a natural compound, vitamin C (Vc), enhances iPSC generation from both mouse and human somatic cells. Vc acts at least in part by alleviating cell senescence, a recently identified roadblock for reprogramming. In addition, Vc accelerates gene expression changes and promotes the transition of pre-iPSC colonies to a fully reprogrammed state. Our results therefore highlight a straightforward method for improving the speed and efficiency of iPSC generation and provide additional insights into the mechanistic basis of the reprogramming process.

Mechanism and methods to induce pluripotency

“…To this end, Vitamin C has been shown to significantly increase the formation of both mouse and human iPSC by suppressing p53 induced cell senescence (Esteban et al, 2010).…”

Reprogramming and Carcinogenesis—Parallels and Distinctions

“…hepatocytes. In general however, lower efficiency and shorter expression kinetics, that would require repeated transductions to maintaining an adequate level of transgene expression makes adenoviral vectors less suitable for the task (Esteban et al, 2010;Sommer et al, 2009). …”

“…As already mentioned, current methods of protein-based reprogramming are several order of magnitudes less inefficient that lentiviral delivery of Yamanaka factors (Bass et al, 2009;Esteban et al, 2010). Typically, synthesized in bacteria Yamanaka factors are modified so that they express basic amino acids-or other transport peptides enabling to cross the cell membrane (Hauff et al, 2005).…”

“…To enhance the reprogramming of cells one may target p53 pathway in a safer way, by carrying-out the process under hypoxic conditions (Bae et al, 2012;Yoshida et al, 2009) or in the presence of ascorbic acid (Esteban et al, 2010). Alternatively, inhibition of p53 is achieved by the increase of expression of SV40 large T antigen or Rem2 GTPase (reviewed in (Stadtfeld and Hochedlinger, 2010)).…”

Non-viral iPSCs: a safe way for therapy?

“…Of note, the Ding's team reported a chemical cocktail, including Butyrate (an HDAC inhibitor), CHIR99021 (a GSK-3β inhibitor), Parnate (a histone lysine demethylase inhibitor), PD0325901 (a MEK inhibitor), A8301 (a TGFβ inhibitor) and PS48 (a phosphoinositide-dependent protein kinase-1 activator), reprogrammed human somatic cells into iPSCs with a single factor OCT4 (Zhu et al, 2010), raising the possibility to completely remove protein factors during reprogramming. Among the molecules modulating specific signaling pathway or epigenetic state, ascorbic acid (Vitamin C, VC) is a star chemical, which enhanced reprogramming of mouse somatic cells (the human iPSCs culture medium contains VC) (Esteban et al, 2010). The mechanism of VC's function may link to its downstream factor Jhdm1a/1b, a histone demethylase responsible for H3K36me2 or H3K36me3 demethylation which in turn accelerates cell proliferation by repressing the Ink4/Arf locus (Wang et al, 2011).…”