title: Proliferation rate of somatic cells affects reprogramming efficiency.
abstract: The discovery of induced pluripotent stem (iPS) cells provides not only new approaches for cell replacement therapy, but also new ways for drug screening. However, the undefined mechanism and relatively low efficiency of reprogramming have limited the application of iPS cells. In an attempt to further optimize the reprogramming condition, we unexpectedly observed that removing c-Myc from the Oct-4, Sox-2, Klf-4, and c-Myc (OSKM) combination greatly enhanced the generation of iPS cells. The iPS cells generated without c-Myc attained salient pluripotent characteristics and were capable of producing full-term mice through tetraploid complementation. We observed that forced expression of c-Myc induced the expression of many genes involved in cell cycle control and a hyperproliferation state of the mouse embryonic fibroblasts during the early stage of reprogramming. This enhanced proliferation of mouse embryonic fibroblasts correlated negatively to the overall reprogramming efficiency. By applying small molecule inhibitors of cell proliferation at the early stage of reprogramming, we were able to improve the efficiency of iPS cell generation mediated by OSKM. Our data demonstrated that the proliferation rate of the somatic cell plays critical roles in reprogramming. Slowing down the proliferation of the original cells might be beneficial to the induction of iPS cells.
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092; National Center for Drug Screening, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Yongyu
authors: Y
authors: Xu
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092; National Center for Drug Screening, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Xiaoyuan
authors: X
authors: Wei
authors: National Center for Drug Screening, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Min
authors: M
authors: Wang
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092. Electronic address: ru.zhang@tongji.edu.cn.
authors: Ru
authors: R
authors: Zhang
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092; National Center for Drug Screening, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Yanbin
authors: Y
authors: Fu
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092; National Center for Drug Screening, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Mingzhe
authors: M
authors: Xing
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092.
authors: Qiuhong
authors: Q
authors: Hua
authors: Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092; National Center for Drug Screening, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xxie@mail.shcnc.ac.cn.
authors: Xin
authors: X
authors: Xie
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D016923:Cell Death; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005816:Genetic Complementation Test; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011003:Ploidies; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012190:Retroviridae / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D000469:Alkaline Phosphatase