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| Status |
Public on Apr 06, 2022 |
| Title |
OCT4-free reprogramming of human fibroblasts into pluripotent stem cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Replacing the transcription factor OCT4, one of the master pluripotency regulators, by small molecules has been a long standing challenge to establish small molecule based reprogramming for the generation of human chemically induced pluripotent stem cells (hciPSCs). Using a cell-based high throughput screen, we have previously identified a new series of OCT4-inducing compounds (O4Is). In this paper, we prepared metabolically stable analogues, including O4I4, which strongly activate pluripotency-associated signaling. In combination with a transcription factor cocktail of SOX2, KLF4, MYC, and LIN28 (collectively referred to as CSKML) we achieved to reprogram human fibroblasts into a stable and authentic pluripotent state independent of exogenous OCT4. Transcriptomic analysis of fibroblasts reprogrammed by this approach revealed that O4I4 activated bone morphogenetic protein (BMP)/SMAD/ID signaling at the early stage of reprogramming and subsequent expression of the chromatin modifier, high mobility group A1 (HMGA1), resulting in re-activation of endogenous OCT4 to initiate the reprogramming process. Consistently, chemical or genetic inhibition of BMP/SMAD/ID or HMGA1 was found to block cellular reprogramming. In C.elegans and Drosophila, O4I4 expanded life spans in a BMP-signaling pathway-dependent manner. Given limitations of OCT4-based reprogramming, our findings provide an alternative to OSKM-mediated iPSC generation, and importantly unravel previously-unrecognized molecular mechanisms of pluripotency in the context of regenerative medicine and rejuvenation therapy.
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| Overall design |
RNA was obtained from treated and non-treated human fibroblast and fibroblast-derived induced Pluripotent Stem Cells and treated with an episomal constrcuts of Oct4, Sox2, Klf4 and c-Myc in addition to O4I3
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| Contributor(s) |
Gama-Brambila RA, Kang H, Dabiri Y, Taškova K, van Oosten LN, Mrowka R, Utikal J, Andrade-Navarro MA, Wang J, Wölfl S, Zhou J, Cheng X |
| Citation missing |
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| Submission date |
Apr 04, 2022 |
| Last update date |
Apr 07, 2022 |
| Contact name |
Xinlai Cheng |
| E-mail(s) |
cheng@pharmchem.uni-frankfurt.de
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| Phone |
0049 69 79842718
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| Organization name |
Goethe Frankfurt University. BMLS
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| Department |
Chemical Biology
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| Lab |
AK Cheng
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| Street address |
Max-von-Laue-Strasse 15. R. 3.652
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| City |
Frankfurt am Main |
| State/province |
Hessen |
| ZIP/Postal code |
60438 |
| Country |
Germany |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA823052 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE200136_Gama_et_al._all.qnorm.xlsx |
44.3 Mb |
(ftp)(http) |
XLSX |
| GSE200136_Gama_et_al._all.raw.xlsx |
47.0 Mb |
(ftp)(http) |
XLSX |
| GSE200136_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE200136_non_normalized.txt.gz |
4.3 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
| Processed data are available on Series record |
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