title: 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.
authors: State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Quan
authors: Q
authors: Wang
authors: Xinxiu
authors: X
authors: Xu
authors: Jun
authors: J
authors: Li
authors: Jing
authors: J
authors: Liu
authors: Haifeng
authors: H
authors: Gu
authors: Ru
authors: R
authors: Zhang
authors: Jiekai
authors: J
authors: Chen
authors: Yin
authors: Y
authors: Kuang
authors: Jian
authors: J
authors: Fei
authors: Cong
authors: C
authors: Jiang
authors: Ping
authors: P
authors: Wang
authors: Duanqing
authors: D
authors: Pei
authors: Sheng
authors: S
authors: Ding
authors: Xin
authors: X
authors: Xie
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D054337:Cell Dedifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D008094:Lithium; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating