Abstract
Mouse somatic cells can be chemically reprogrammed into pluripotent stem cells (CiPSCs) through an intermediate extraembryonic endoderm (XEN)-like state. However, it is elusive how the chemicals orchestrate the cell fate alteration. In this study, we analyze molecular dynamics in chemical reprogramming from fibroblasts to a XEN-like state. We find that Sox17 is initially activated by the chemical cocktails, and XEN cell fate specialization is subsequently mediated by Sox17 activated expression of other XEN master genes, such as Sall4 and Gata4. Furthermore, this stepwise process is differentially regulated. The core reprogramming chemicals CHIR99021, 616452 and Forskolin are all necessary for Sox17 activation, while differently required for Gata4 and Sall4 expression. The addition of chemical boosters in different phases further improves the generation efficiency of XEN-like cells. Taken together, our work demonstrates that chemical reprogramming is regulated in 3 distinct “prime–specify–transit” phases initiated with endogenous Sox17 activation, providing a new framework to understand cell fate determination.
Highlights
Mouse somatic cells can be chemically reprogrammed into pluripotent stem cells (CiPSCs) through an intermediate extraembryonic endoderm (XEN)-like state
An extraembryonic endoderm (XEN)-like state bridges the chemical reprogramming towards chemically reprogrammed into pluripotent stem cells (CiPSCs) from different somatic cell types[4,5]
We revealed that cell fate transition was primed by endogenously expressed Sox[17], which mediated further hierarchical activation of master transcription factors in chemical reprogramming
Summary
Mouse somatic cells can be chemically reprogrammed into pluripotent stem cells (CiPSCs) through an intermediate extraembryonic endoderm (XEN)-like state. It is elusive how the chemicals orchestrate the cell fate alteration. Unlike the master genes used in transgenic reprogramming, which are associated with the target cell type, these chemicals always target signaling pathways that play roles in different cell types and are not associated with any specific cell lineage It is still unclear how the chemical cocktails determine the target cell type, and the molecular dynamics during chemically induced cell fate transition are still elusive[23]
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