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Chemical reversion of mouse post-implantation epiblast directly to totipotent-like cells

ABSTRACT: Totipotent cells can give rise to all cell types in an organism. Mouse totipotent-like cells (TLCs) have been generated from undifferentiated pluripotent embryonic stem cells (ESCs). However, it remains unknown whether TLCs can be generated from differentiated cells. Here, we report a novel chemically defined medium which can efficiently induce TLCs from differentiation-committed cells including epiblast-like cells (EpiLCs) and post-implantation epiblast. Comparatively, MERVL-GFP positive cells induced from differentiated cells exhibit closer transcriptome characteristics to 2-cell (2C) embryos in contrast to those induced from pluripotent ESCs. Moreover, differentiated cells exhibit distinct reprogramming kinetics and pathways to TLCs compared to ESCs. They are directly and rapidly reprogrammed into TLCs without passing through a pluripotent intermediate. Notably, TLCs were generated from post-implantation epiblast and demonstrated the capacity to contribute to both embryonic and extra-embryonic lineages in chimeras. Overall, these findings have significant implications for understanding the mechanism of totipotency acquisition and cell plasticity.

ORGANISM(S): Mus musculus

PROVIDER: GSE285365 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) exhibit a pluripotent developmental potential, contributing to all embryonic cell types, though rarely to extra-embryonic lineages. Unexpectedly, rare, totipotent-like stem cells have been identified in cultured ESC populations, suggesting the existence of a discrete molecular pathway that regulates the transition between totipotency and pluripotency in vitro. Here, we identify a single miRNA, miR-34a, whose deficiency in mouse pluripotent stem cells expands cell fate potential, giving rise to both embryonic and extra-embryonic lineages in vitro and in vivo. The expression profiles of the totipotent-like miR-34a-knockout murine pluripotent stem cells are characterized by a strong induction of MERVL endogenous retroviruses, a key molecular hallmark shared with totipotent mouse 2-cell blastomeres and totipotent-like mouse ESCs. In all three cell types, a subset of MERVL elements promotes the expression of specific isoforms of the proximal protein-coding genes. We demonstrate that miR-34a represses MERVL expression through transcriptional regulation, at least in part, by directly targeting the transcription factor GATA-binding protein 2 (Gata2). Since MERVL activation correlated precisely with the totipotent-like state, we hypothesized that the miR-34a/Gata2 pathway that regulates MERVL expression in ESCs/iPSCs also regulates the acquisition of totipotency in culture. Consistent with this hypothesis, gata2 knock-down in miR-34a-knockout mouse pluripotent stem cells not only reduced MERVL expression, but also abolished the expanded cell fate potential of these cells both in vitro and in vivo. Taken together, our findings not only provide key insights into the functional importance of miR-34a in restricting the totipotent cell fate potential of pluripotent stem cells, but also elucidate the underlying molecular basis by which miR-34a regulates the developmental potentials of ESCs/iPSCs.

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Chemical reversion of mouse post-implantation epiblast directly to totipotent-like cells

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