OCT6 inhibits differentiation of porcine-induced pluripotent stem cells through MAPK and PI3K signaling regulation

Yang, Xinchun; Wu, Xiaolong; Li, Wenhao; Wu, Xue-Ru; Shen, Qian-Yan; Li, Yunxiang; Peng, Sha; Hua, Jinlian

doi:10.24272/j.issn.2095-8137.2022.220

Cited by 10 publications

(5 citation statements)

References 64 publications

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“…Whether this difference relies on the different types of pluripotency presented by human and mouse PSCs, i.e., naïve vs. primed, remains to be fully investigated. Indeed, Oct6 has recently been shown to block the differentiation of porcine iPSCs, which display a primed pluripotency phenotype 32 . However, its precise role in the context of mouse PSC differentiation and the dissolution of naïve pluripotency circuitry remains largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressing Nanog and activating a formative state gene regulatory network

Waisman,

Sevlever,

Saulnier

et al. 2024

Sci Rep

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In the mouse embryo, the transition from the preimplantation to the postimplantation epiblast is governed by changes in the gene regulatory network (GRN) that lead to transcriptional, epigenetic, and functional changes. This transition can be faithfully recapitulated in vitro by the differentiation of mouse embryonic stem cells (mESCs) to epiblast-like cells (EpiLCs), that reside in naïve and formative states of pluripotency, respectively. However, the GRN that drives this conversion is not fully elucidated. Here we demonstrate that the transcription factor OCT6 is a key driver of this process. Firstly, we show that Oct6 is not expressed in mESCs but is rapidly induced as cells exit the naïve pluripotent state. By deleting Oct6 in mESCs, we find that knockout cells fail to acquire the typical morphological changes associated with the formative state when induced to differentiate. Additionally, the key naïve pluripotency TFs Nanog, Klf2, Nr5a2, Prdm14, and Esrrb were expressed at higher levels than in wild-type cells, indicating an incomplete dismantling of the naïve pluripotency GRN. Conversely, premature expression of Oct6 in naïve cells triggered a rapid morphological transformation mirroring differentiation, that was accompanied by the upregulation of the endogenous Oct6 as well as the formative genes Sox3, Zic2/3, Foxp1, Dnmt3A and FGF5. Strikingly, we found that OCT6 represses Nanog in a bistable manner and that this regulation is at the transcriptional level. Moreover, our findings also reveal that Oct6 is repressed by NANOG. Collectively, our results establish OCT6 as a key TF in the dissolution of the naïve pluripotent state and support a model where Oct6 and Nanog form a double negative feedback loop which could act as an important toggle mediating the transition to the formative state.

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Section: Discussionmentioning

confidence: 99%

The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressing Nanog and activating a formative state gene regulatory network

Waisman,

Sevlever,

Saulnier

et al. 2024

Sci Rep

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show abstract

“…Whether this difference relies on the different types of pluripotency presented by human and mouse PSCs, i.e., naïve vs. primed, remains to be fully investigated. Indeed, Oct6 has recently been shown to block the differentiation of porcine IPSCs, which display a primed pluripotency phenotype (Yang et al, 2022). However, its precise role in the context of mouse PSC differentiation and the dissolution of naïve pluripotency circuitry remains largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressingNanogand activating a formative state gene regulatory network

Waisman,

Sevlever,

Saulnier

et al. 2023

Preprint

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Animal development relies on complex gene regulatory networks (GRNs) that govern the nearly irreversible changes that occur during cell differentiation. In this work we aimed to determine key transcription factors (TFs) associated with the dissolution of the naive pluripotent state and the acquisition of a formative identity. We identified OCT6 as one of the earliest TFs induced during the onset of mouse embryonic stem cell (mESCs) differentiation. To investigate its role, we generated an Oct6 knockout mESC line, which failed to acquire the characteristic cell morphology associated with the formative state. Transcriptome analysis of differentiating cells revealed nearly 300 differentially expressed genes compared to wild-type cells, including pluripotency TFs Nanog, Klf2, Nr5a2, Prdm14, and Esrrb, that failed to correctly downregulate. Notably, premature expression of OCT6 in naive cells triggered a rapid morphological transformation mirroring differentiation, accompanied by self-induction of Oct6 and expression of TFs such as Sox3, Zic2/3, Foxp1, as well as the formative genes Dnmt3A and FGF5. Strikingly, the majority of OCT6-expressing cells did not express NANOG. Gene expression and single molecule RNA-FISH analysis confirmed that this regulation was at the transcriptional level. Collectively, our results establish OCT6 as a key TF in the dissolution of the naive pluripotent state and support a model where Oct6 and Nanog form a double negative feedback loop which could act as a toggle switch important for the transition to the formative state.

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“…The sgRNA was designed using http://crispor.tefor.net/crispor.py 20 . The primers used in this study are provided in Table S1, and the core coding sequence of the recombinant vector was verified by sequencing 21 …”

Section: Methodsmentioning

confidence: 99%

Induction of lung progenitor cell‐like organoids by porcine pluripotent stem cells

Yang,

Wu,

Wang

et al. 2024

The FASEB Journal

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Organoids are in vitro 3D models that are generated using stem cells to study organ development and regeneration. Despite the extensive research on lung organoids, there is limited information on pig lung cell generation or development. Here, we identified five epithelial cell types along with their characteristic markers using scRNA‐seq. Additionally, we found that NKX2.1 and FOXA2 acted as the crucial core transcription factors in porcine lung development. The presence of SOX9/SOX2 double‐positive cells was identified as a key marker for lung progenitor cells. The Monocle algorithm was used to create a pseudo‐temporal differentiation trajectory of epithelial cells, leading to the identification of signaling pathways related to porcine lung development. Moreover, we established the differentiation method from porcine pluripotent stem cells (pPSCs) to SOX17+FOXA2+ definitive endoderm (DE) and NKX2.1+FOXA2+CDX2− anterior foregut endoderm (AFE). The AFE is further differentiated into lung organoids while closely monitoring the differentiation process. We showed that NKX2.1 overexpression facilitated the induction of lung organoids and supported subsequent lung differentiation and maturation. This model offers valuable insights into studying the interaction patterns between cells and the signaling pathways during the development of the porcine lung.

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OCT6 inhibits differentiation of porcine-induced pluripotent stem cells through MAPK and PI3K signaling regulation

Cited by 10 publications

References 64 publications

The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressing Nanog and activating a formative state gene regulatory network

The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressing Nanog and activating a formative state gene regulatory network

The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressingNanogand activating a formative state gene regulatory network

Induction of lung progenitor cell‐like organoids by porcine pluripotent stem cells

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