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Development of a next-generation endogenous OCT4 inducer and its anti-aging effect in vivo

The identification of small molecules capable of replacing transcription factors has been a longstanding challenge in the generation of human chemically induced pluripotent stem cells (iPSCs). Recent studies have shown that ectopic expression of OCT4, one of the master pluripotency regulators, compr...

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Main Authors: Han, Kang (Author) , Hasselbeck, Sebastian (Author) , Taškova, Katerina (Author) , Wang, Nessa (Author) , Oosten, Luuk N. van (Author) , Mrowka, Ralf (Author) , Utikal, Jochen (Author) , Andrade-Navarro, Miguel A. (Author) , Wang, Jichang (Author) , Wölfl, Stefan (Author) , Cheng, Xinlai (Author)
Format: Article (Journal)
Language:English
Published: 28 May 2023
In: European journal of medicinal chemistry
Year: 2023, Volume: 257, Pages: 1-14
ISSN:1768-3254
DOI:10.1016/j.ejmech.2023.115513
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejmech.2023.115513
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0223523423004798
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Author Notes:Han Kang, Sebastian Hasselbeck, Katerina Taškova, Nessa Wang, Luuk N. van Oosten, Ralf Mrowka, Jochen Utikal, Miguel A. Andrade-Navarro, Jichang Wang, Stefan Wölfl, Xinlai Cheng
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Summary:The identification of small molecules capable of replacing transcription factors has been a longstanding challenge in the generation of human chemically induced pluripotent stem cells (iPSCs). Recent studies have shown that ectopic expression of OCT4, one of the master pluripotency regulators, compromised the developmental potential of resulting iPSCs, This highlights the importance of finding endogenous OCT4 inducers for the generation of clinical-grade human iPSCs. Through a cell-based high throughput screen, we have discovered several new OCT4-inducing compounds (O4Is). In this work, we prepared metabolically stable analogues, including O4I4, which activate endogenous OCT4 and associated signaling pathways in various cell lines. By combining these with a transcription factor cocktail consisting of SOX2, KLF4, MYC, and LIN28 (referred to as "CSKML") we achieved to reprogram human fibroblasts into a stable and authentic pluripotent state without the need for exogenous OCT4. In Caenorhabditis elegans and Drosophila, O4I4 extends lifespan, suggesting the potential application of OCT4-inducing compounds in regenerative medicine and rejuvenation therapy.
Item Description:Online verfügbar 24 May 2023, Version des Artikels 28 May 2023
Gesehen am 25.09.2023
Physical Description:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2023.115513

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