Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells

Abstract

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. The low efficiency of reprogramming and genomic integration of oncogenes and viral vectors limited the potential application of iPSCs. Here we report that Lithium (Li), a drug used to treat mood disorders, greatly enhances iPSC generation from both mouse embryonic fibroblast and human umbilical vein endothelial cells. Li facilitates iPSC generation with one (Oct4) or two factors (OS or OK). The effect of Li on promoting reprogramming only partially depends on its major target GSK3β. Unlike other GSK3β inhibitors, Li not only increases the expression of Nanog, but also enhances the transcriptional activity of Nanog. We also found that Li exerts its effect by promoting epigenetic modifications via downregulation of LSD1, a H3K4-specific histone demethylase. Knocking down LSD1 partially mimics Li's effect in enhancing reprogramming. Our results not only provide a straightforward method to improve the iPSC generation efficiency, but also identified a histone demethylase as a critical modulator for somatic cell reprogramming.

Generation of pluripotent stem cells without the use of genetic material

“…80 The anti-psychotic drug lithium chloride (LiCl) can accelerate the generation of mouse and human iPSCs. 70 The effect of LiCl on promoting reprogramming is partially dependent on its role as a GSK-3b inhibitor. However, LiCl also upregulates Nanog, which has not been observed after the treatment of somatic cells with other GSK-3b inhibitors.…”

“…15,[69][70][71] Compound 616452 can replace Sox2 in the MEF reprogramming. However, 616452 does not actually act by inducing Sox2 expression in the target cells; rather, it enables reprogramming through the induction of Nanog transcription.…”

“…17 RG108, a DNMT inhibitor, can replace Oct4 during mouse skeletal muscle cell reprogramming into miPSCs where skeletal muscle cells endogenously express Sox2, Klf4, and c-Myc. 70 Figure 2 shows the chemical scheme of small molecules that may functionally replace Oct4 and Klf4 during somatic cell reprogramming into iPSCs.…”

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

“…Other histone modification enzymes, such as LSD1 (a H3K4 demethylase), are also involved in reprogramming. Small molecules targeting LSD1, including parnate and LiCl, have also been reported to facilitate iPSC induction [59,60] . In addition, Jhdm1a/1b, two known vitamin-C-dependent H3K36 demethylases, have been found to critically regulate vitamin C-enhanced reprogramming [61] .…”

A special issue on cell signaling, disease, and stem cells

“…We chose to highlight these stem cell papers in this special issue as stem cell research is intrinsically connected to the study of cell signaling and disease. The collection of a large number of stem cell papers also reflects the fact that stem cell research has become an important part of the growing content of Cell Research, as highlighted by a large number of important discoveries published in the journal in the past year alone, such as the successful generation of iPS cells with a single factor Oct4 [3,4], efficient generation of human iPS cells from blood cells via a non-integrating method [5], generation of functional platelets from hESCs [6], directed differentiation of atrial and ventricular myocytes from hESCs [7], the successful generation of ovine, hircine and bovine iPS cells [8][9][10], somatic cell reprogramming using electrofused blastomeres [11], improved methods for iPS cell generation [12,13], gener-ating iPS cells using Bmi1 [14], comprehensive analyses of chromatin state dynamics in hESC differentiation [15], characterization of neuroblasts in the adult human brain [16], identification of lectin biomarkers for human pluripotent stem cell isolation [17], and efficient correction of disease-causing genetic mutations in patient iPS cells [18].…”