Induction of mouse totipotent stem cells by a defined chemical cocktail

Hu, Yanyan; Yang, Yuanyuan; Tan, Pengcheng; Zhang, Yuxia; Han, MeiLan K.; Yu, Jiawei; Zhang, Xin; Jia, Zeran; Wang, Dan; Li, Yinqing; Ma, Tianhua; Liu, Kang; Ding, Sheng

doi:10.1038/s41586-022-04967-9

Cited by 50 publications

(32 citation statements)

References 30 publications

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“…We identified critical genomic loci and proteins that provide a rich resource for further investigations as the potential molecular targets endowing EPSCs with superior developmental potential over ESCs ( Fig 6 ). Similar studies are warranted for other currently available totipotent-like cells, including 2CLCs ( Macfarlan et al, 2012 ), totipotent blastomere-like cells (TBLCs) ( Shen et al, 2021 ), totipotent-like stem cells (TLSCs) ( Yang et al, 2022 ), TPSCs ( Xu et al, 2022 ), chemically induced totipotent stem cells (ciTotiSCs) ( Hu et al, 2022 ), and human 8CLCs ( Mazid et al, 2022 ; Taubenschmid-Stowers et al, 2022 ). Ultimately, we will be able to capture authentic totipotent stem cells in vitro ( Malik & Wang, 2022 ) and likely also reveal alternative paths to totipotency and/or alternative totipotent states.…”

Section: Discussionmentioning

confidence: 89%

“…Such studies will thus delineate if and how Zfp281 and RAR-RXR family proteins may contribute to the expanded potential of EPSCs, particularly considering activation of RARγ signaling are important for inducing and maintaining totipotent features of TPSCs (Xu et al, 2022) and both Zfp281 and RAR-RXR family proteins may play a role in cell division and DNA replication-free reprogramming of somatic nuclei for embryonic transcription (Tomikawa et al, 2021). Recently Hu et al succeeded in capturing 2CLCs in vitro using three chemicals including TTNPB (RAR-agonist) (Hu et al, 2022), thus corroborating our findings and strengthening the demand to explore the possible role of these factors in expanded potential of EPSCs.…”

Section: Discussionmentioning

confidence: 99%

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Comparative functional genomics identifies unique molecular features of EPSCs

et al. 2022

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Extended pluripotent or expanded potential stem cells (EPSCs) possess superior developmental potential to embryonic stem cells (ESCs). However, the molecular underpinning of EPSC maintenance in vitro is not well defined. We comparatively studied transcriptome, chromatin accessibility, active histone modification marks, and relative proteomes of ESCs and the two well-established EPSC lines to probe the molecular foundation underlying EPSC developmental potential. Despite some overlapping transcriptomic and chromatin accessibility features, we defined sets of molecular signatures that distinguish EPSCs from ESCs in transcriptional and translational regulation as well as metabolic control. Interestingly, EPSCs show similar reliance on pluripotency factors Oct4, Sox2, and Nanog for self-renewal as ESCs. Our study provides a rich resource for dissecting the regulatory network that governs the developmental potency of EPSCs and exploring alternative strategies to capture totipotent stem cells in culture.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Comparative functional genomics identifies unique molecular features of EPSCs

et al. 2022

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“…Not only transcriptional and developmental potentials but also DNA methylation, histone modification, glycolysis, and protein synthesis exhibit similarities to 2C embryos in RA-induced 2C-like cells ( Wang et al, 2021 ). However, RA-treated cells gradually died or differentiated, and they failed to maintain a stable totipotent state ( Hu et al, 2022 ). In the pluripotent state, RA counteracted the differentiation and maintains pluripotency, through the activation of WNT signaling ( Wang et al, 2008 ), Nanog expression ( Chen et al, 2007 ), and phosphoinositide 3-kinase (PI3K) activation ( Chen and Khillan, 2010 ).…”

Section: Regulation Of the Signaling Pathwaymentioning

confidence: 99%

“…However, both TBLCs and TLSCs differentiated poorly toward some of PrE- and TE-derived lineages ( Shen et al, 2021 ; Yang et al, 2022 ), questioning the developmental potential of these in vivo totipotent cells. Recently, the Ding laboratory recently generated a culture condition to reprogram cells to chemically induce totipotent stem cells (ciTotiSCs), resembling mouse totipotent 2C embryo stage cells at transcriptional, epigenetic, and metabolic levels ( Hu et al, 2022 ). Excitingly, the culture conditions in the Deng laboratory can derive totipotent potential stem (TPS) cells from 2C embryos.…”

Section: Introductionmentioning

confidence: 99%

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

Liang

2022

Front. Cell Dev. Biol.

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Totipotency represents the highest developmental potency. By definition, totipotent stem cells are capable of giving rise to all embryonic and extraembryonic cell types. In mammalian embryos, totipotency occurs around the zygotic genome activation period, which is around the 2-cell stage in mouse embryo or the 4-to 8-cell stage in human embryo. Currently, with the development of in vitro totipotent-like models and the advances in small-scale genomic methods, an in-depth mechanistic understanding of the totipotency state and regulation was enabled. In this review, we explored and summarized the current views about totipotency from various angles, including genetic and epigenetic aspects. This will hopefully formulate a panoramic view of totipotency from the available research works until now. It can also help delineate the scaffold and formulate new hypotheses on totipotency for future research works.

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“…However, more comprehensive analysis, and additional optimizations are required to test the proposed cocktail with other somatic cells from humans and different species for reprogramming efficiency. Along similar lines, a recent report describes the use of three small molecules alone to generate 'totipotent' mouse cells from pluripotent stem cells (Hu et al 2022). Furthermore, more insight is required to determine whether the small molecules used have potential off target effects prior to evaluating their clinical implications.…”

Section: Open Accessmentioning

confidence: 99%

Chemical journey of somatic cells to pluripotency

Abbey

2022

Cell Regen

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Reprogramming somatic cells to pluripotent stem cells has revolutionized the biomedical field by providing enormous hopes and opportunities for the regeneration of tissues and organs for transplantation. Using a small molecule cocktail of epigenetic modifiers and cell signalling inhibitors, a chemical-based easy and controllable technique for converting human somatic cells into chemically induced pluripotent stem cells was recently reported (Guan, Nature 605:325–31, 2022). This novel approach offers well-defined, safe, simple, easy, and clinical-grade manufacturing strategies for modifying the fate of human cells required for regenerative therapeutics.

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Induction of mouse totipotent stem cells by a defined chemical cocktail

Cited by 50 publications

References 30 publications

Comparative functional genomics identifies unique molecular features of EPSCs

Comparative functional genomics identifies unique molecular features of EPSCs

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

Chemical journey of somatic cells to pluripotency

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