Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming

  • Cell Stem Cell. 2023 Mar 11;S1934-5909(23)00069-3. doi: 10.1016/j.stem.2023.02.008.
Shijia Liuyang  1 ,  Guan Wang  2 ,  Yanglu Wang  3 ,  Huanjing He  1 ,  Yulin Lyu  4 ,  Lin Cheng  1 ,  Zhihan Yang  1 ,  Jingyang Guan  1 ,  Yao Fu  1 ,  Jialiang Zhu  1 ,  Xinxing Zhong  2 ,  Shicheng Sun  1 ,  Cheng Li  4 ,  Jinlin Wang  5 ,  Hongkui Deng  6
Affiliations
  • 1. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 2. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
  • 3. Academy for Advanced Interdisciplinary Studies, The Center for Biomed-X Research, Peking University, Beijing, China.
  • 4. School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China.
  • 5. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. Electronic address: [email protected].
  • 6. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. Electronic address: [email protected].
PMID: 36944335 DOI: 10.1016/j.stem.2023.02.008
Abstract

We recently demonstrated the chemical reprogramming of human somatic cells to pluripotent stem cells (hCiPSCs), which provides a robust approach for cell fate manipulation. However, the utility of this chemical approach is currently hampered by slow kinetics. Here, by screening for small molecule boosters and systematically optimizing the original condition, we have established a robust, chemically defined reprogramming protocol, which greatly shortens the induction time from ∼50 days to a minimum of 16 days and enables highly reproducible and efficient generation of hCiPSCs from all 17 tested donors. We found that this optimized protocol enabled a more direct reprogramming process by promoting cell proliferation and Oxidative Phosphorylation metabolic activities at the early stage. Our results highlight a distinct chemical reprogramming pathway that leads to a shortcut for the generation of human pluripotent stem cells, which represents a powerful strategy for human cell fate manipulation.

Keywords
chemical reprogramming; chemically defined; hCiPSCs; human adult somatic cells; oxidative phosphorylation; pluripotency; small molecules.
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