A XEN-like State Bridges Somatic Cells to Pluripotency during Chemical Reprogramming

Zhao, Yang; Zhao, Ting; Guan, Jingyang; Zhang, Xu; Fu, Yao; Ye, Junqing; Zhu, Jialiang; Meng, Gaofan; Ge, Jian; Yang, Shiwu; Cheng, Lin; Du, Yifei; Zhao, Chenyang; Wang, Ting; Su, Linlin; Yang, Weifeng; Deng, Hongkui

doi:10.1016/j.cell.2015.11.017

Cited by 214 publications

(246 citation statements)

References 30 publications

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“…The study published by Zhao et al [5] now confirms that CiPSCs are derived via a XEN-like state, which allowed them to enhance the efficiency of the chemical-induced reprogramming by dissection of the cell fate transitions. They first observed that CiPSCs emerged from epitheloid colonies that expressed XEN markers and knocking these markers down hampered CiPSC formation.…”

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confidence: 79%

“…Although the past decade has seen methodological improvements, generation of iPSCs still requires genetic manipulation that hinders their therapeutic application. The chemical cocktail developed by Zhao et al [5] of Deng's group circumvents this problem.…”

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confidence: 99%

“…They first performed lineage tracing experiments via fibroblast specific protein 1 (Fsp1) to confirm that CiPSCs can be indeed generated from differentiated fibroblasts rather than a specific cell type amenable to pluripotency within the culture. Neural stem cells isolated from mouse brains by SSEA1 surface marker required another chemical, Ch55 (5), in addition to VC6TFE and decreased dosage of 616452 (6). They then tried to reprogram epithelial cells isolated from the small intestine based on the markers, EpCAM or VILLIN.…”

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confidence: 99%

“…However, although the developmental fates of epiblast and XEN are divergent from each other in vivo , XEN cells have been derived from PSCs in vitro [12]. These observations combined with the observation of XEN-to-PSC transition by Zhao et al [5] indicate that cells can be more plastic in vitro, and the chemical cocktail of Deng's group might be hijacking such plasticity of XEN cells instead of reversing ontogeny. It is thus possible that the same principle can be applied to other embryonic sources, such as neural crest cells, to achieve pluripotency by hijacking their plasticity as an intermediate state to pluripotency in vitro.…”

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confidence: 99%

“…Another limiting factor is the long duration. CiPSC formation from fibroblasts takes 40 days even with the optimized protocol of Zhao et al [5] …”

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confidence: 99%

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The XEN of reprogramming

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Belmonte

2016

Cell Res

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mentioning

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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“…Another limiting factor is the long duration. CiPSC formation from fibroblasts takes 40 days even with the optimized protocol of Zhao et al [5] …”

mentioning

confidence: 99%

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The XEN of reprogramming

Beyret

Belmonte

2016

Cell Res

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Regulation of cardiac fibroblasts reprogramming into cardiomyocyte‐like cells with a cocktail of small molecule compounds

Chang,

Sun,

Tian

et al. 2024

FEBS Open Bio

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Myocardial infarction results in extensive cardiomyocyte apoptosis, leading to the formation of noncontractile scar tissue. Given the limited regenerative capacity of adult mammalian cardiomyocytes, direct reprogramming of cardiac fibroblasts (CFs) into cardiomyocytes represents a promising therapeutic strategy for myocardial repair, and small molecule drugs might offer a more attractive alternative to gene editing approaches in terms of safety and clinical feasibility. This study aimed to reprogram rat CFs into cardiomyocytes using a small molecular chemical mixture comprising CHIR99021, Valproic acid, Dorsomorphin, SB431542, and Forskolin. Immunofluorescence analysis revealed a significant increase in the expression of cardiomyocyte‐specific markers, including cardiac troponin T (cTnT), Connexin 43 (Cx43), α‐actinin, and Tbx5. Changes in intracellular calcium ion levels and Ca2+ signal transfer between adjacent cells were monitored using a calcium ion fluorescence probe. mRNA sequencing analysis demonstrated the upregulation of genes associated with cardiac morphogenesis, myocardial differentiation, and muscle fiber contraction during CF differentiation induced by the small‐molecule compounds. Conversely, the expression of fibroblast‐related genes was downregulated. These findings suggest that chemical‐induced cell fate conversion of rat CFs into cardiomyocyte‐like cells is feasible, offering a potential therapeutic solution for myocardial injury.

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Cell‐Reprogramming‐Inspired Dynamically Responsive Hydrogel Boosts the Induction of Pluripotency via Phase‐Separated Biomolecular Condensates

Zhu

Yan

et al. 2023

Advanced Materials

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Induced pluripotent stem cells (iPSCs) have wide applications in disease modeling, personalized medicine, and tissue engineering. The generation of iPSCs from somatic cells via transcriptional‐factor‐ or chemical molecule‐based approaches are time‐consuming and inefficient. Here, a cell‐reprogramming‐inspired dynamically responsive hydrogel is fabricated via a synthetic‐biology‐based strategy. Human and mouse somatic cells (including senescent cells) are efficiently reprogrammed into iPSCs that exhibit key features of embryonic stem cells. The cell‐reprogramming‐responsive hydrogel possesses dynamic bioresponsiveness, and it faithfully senses metabolic remodeling and extracellular acidification during cell reprogramming, responding by changing its mechanical properties accordingly. Mechanistic study demonstrates that the autonomous change of the mechanical properties of the cell‐reprogramming‐responsive hydrogel elicits the formation of Yes‐associated protein (YAP) biomolecular condensates with the appropriate timing during cell reprogramming, ensuring a faster and more efficient generation of iPSCs than conventional cell reprogramming approach. Taken together, this study reveals the robust induction of pluripotency by coordination of cell‐reprogramming‐inspired dynamically responsive hydrogel and phase‐separated biomolecular condensates.

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A XEN-like State Bridges Somatic Cells to Pluripotency during Chemical Reprogramming

Cited by 214 publications

References 30 publications

The XEN of reprogramming

The XEN of reprogramming

Regulation of cardiac fibroblasts reprogramming into cardiomyocyte‐like cells with a cocktail of small molecule compounds

Cell‐Reprogramming‐Inspired Dynamically Responsive Hydrogel Boosts the Induction of Pluripotency via Phase‐Separated Biomolecular Condensates

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