Video1_Chemical Pretreatment Activated a Plastic State Amenable to Direct Lineage Reprogramming.MP4
Somatic cells can be chemically reprogrammed into a pluripotent stem cell (CiPSC) state, mediated by an extraembryonic endoderm- (XEN-) like state. We found that the chemical cocktail applied in CiPSC generation initially activated a plastic state in mouse fibroblasts before transitioning into XEN-like cells. The plastic state was characterized by broadly activated expression of development-associated transcription factors (TFs), such as Sox17, Ascl1, Tbx3, and Nkx6-1, with a more accessible chromatin state indicating an enhanced capability of cell fate conversion. Intriguingly, introducing such a plastic state remarkably improved the efficiency of chemical reprogramming from fibroblasts to functional neuron-like cells with electrophysiological activity or beating skeletal muscles. Furthermore, the generation of chemically induced neuron-like cells or skeletal muscles from mouse fibroblasts was independent of the intermediate XEN-like state or the pluripotency state. In summary, our findings revealed a plastic chemically activated multi-lineage priming (CaMP) state at the onset of chemical reprogramming. This state enhanced the cells’ potential to adapt to other cell fates. It provides a general approach to empowering chemical reprogramming methods to obtain functional cell types bypassing inducing pluripotent stem cells.
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References
- https://doi.org//10.1016/j.biomaterials.2018.11.037
- https://doi.org//10.1038/nbt.3247
- https://doi.org//10.1016/j.cell.2006.02.041
- https://doi.org//10.1016/j.cell.2012.08.023
- https://doi.org//10.1126/science.aaf1502
- https://doi.org//10.1074/jbc.M117.812537
- https://doi.org//10.1038/cr.2014.32
- https://doi.org//10.1016/j.molcel.2018.04.028
- https://doi.org//10.1038/ncb2164
- https://doi.org//10.1038/cr.2015.99
- https://doi.org//10.1242/dev.081703
- https://doi.org//10.1038/nature08533
- https://doi.org//10.1186/s12864-018-4625-x
- https://doi.org//10.1126/science.1239278
- https://doi.org//10.1016/j.stem.2015.07.006
- https://doi.org//10.1101/gad.253443.114
- https://doi.org//10.1016/j.stem.2014.01.006
- https://doi.org//10.1016/j.molcel.2016.06.035
- https://doi.org//10.1016/j.stem.2017.05.019
- https://doi.org//10.1016/j.stem.2015.06.003
- https://doi.org//10.1038/s41586-020-2201-4
- https://doi.org//10.1038/nbt.3270
- https://doi.org//10.1161/CIRCRESAHA.111.260026
- https://doi.org//10.1016/j.celrep.2016.12.062
- https://doi.org//10.1016/j.cell.2012.11.039
- https://doi.org//10.1093/nar/gku365
- https://doi.org//10.1021/bi902065k
- https://doi.org//10.1016/j.cell.2019.01.006
- https://doi.org//10.1016/j.cell.2009.01.001
- https://doi.org//10.1016/j.cell.2019.05.031
- https://doi.org//10.1016/j.cell.2006.07.024
- https://doi.org//10.1038/s41598-017-04665-x
- https://doi.org//10.1016/j.celrep.2016.06.042
- https://doi.org//10.1016/j.celrep.2014.01.038
- https://doi.org//10.1016/j.stem.2016.06.006
- https://doi.org//10.1016/j.stem.2015.01.013
- https://doi.org//10.1038/s42003-020-01346-w
- https://doi.org//10.1016/j.stemcr.2019.01.003
- https://doi.org//10.1186/gb-2008-9-9-r137
- https://doi.org//10.1016/j.stem.2018.05.025
- https://doi.org//10.1016/j.cbpa.2019.04.025
- https://doi.org//10.1016/j.cell.2015.11.017
- https://doi.org//10.1038/nature13020
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