Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin

Malaguti, Mattias; Nistor, Paul; Blin, Guillaume; Pegg, Amy; Zhou, Xiaohu; Lowell, Sally

doi:10.7554/elife.01197

Cited by 69 publications

(104 citation statements)

References 59 publications

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“…Thus, it appears that silencing the Id1 gene can improve the neural differentiation rate of MSCs, consistent with a report that neural differentiation can be increased by suppressing Id1 expression in zebrafish [32]. It has been reported that high expression of Id1 promotes cell proliferation and inhibits cell differentiation [33,34], which is in agreement with the reports that overexpression of Id1 maintains the undifferentiated state by sustaining pluripotency markers [35] and preventing commitment to a neural fate [36]. The bHLH family consists of two classes of transcription regulators: inhibitors (such as Hes and Id) and activators (such as Mash1, Math1 and NeuroD).…”

Section: Neural Differentiation and Immunocytochemistrysupporting

confidence: 80%

The effect ofId1gene silencing on the neural differentiation of MSCs

Song

et al. 2017

Biotechnology & Biotechnological Equipment

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We aimed to construct a highly efficient, lentivirus-mediated vector for RNA interference (RNAi) silencing of the Id1 gene and to examine whether silencing of this gene promotes the neural differentiation of mesenchymal stem cells (MSCs). Three short hairpin RNA sequences targeting the coding region of the Id1 gene and one negative control (NC) sequence were designed. After monophosphorylation, these sequences were introduced into lentiviral vectors containing enhanced green fluorescent protein (EGFP) using the restriction enzyme BsmBI to construct the recombinant vectors pWSLV-EGF-shId1 (1-3) and pWSLV-EGF-NC. These recombinant lentivirus vectors were transfected into H9C2 cells to assess the silencing effect of the shId1 (1-3) sequences on the Id1 gene. Subsequently, pWSLV-EGF-NC and pWSLV-EGF-shId1 which exhibited the strongest silencing effect were transfected into the packaging cell line 293 FT. After determining the viral titers, the cultured MSCs were infected with the lentivirus (multiplicity of infection, MOI D 10). Real-time polymerase chain reaction (PCR) and Western blotting were used to examine the amounts of Id1 mRNA and protein, respectively, in the transfected MSCs, and the results revealed that Id1 expression was markedly inhibited. Finally, MSCs were treated with the growth factors EGF and bFGF in conjunction with ligustrazine to induce their differentiation into neuron-like cells. The expression of NSE/MAP-2/Nestin was detected using immunocytochemistry and real-time PCR, which revealed that the rate of neural differentiation in the pWSLV-EGF-shId1 group was higher than that of the other groups, as was NSE/MAP-2 expression. Thus, Id1 gene silencing promotes the neural differentiation of MSCs.

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Section: Neural Differentiation and Immunocytochemistrysupporting

confidence: 80%

The effect ofId1gene silencing on the neural differentiation of MSCs

Song

et al. 2017

Biotechnology & Biotechnological Equipment

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“…In adherent culture in the absence of serum factors, ES cells progress from naïve pluripotency into a population that resembles the early post‐implantation formative epiblast 16, 45, 81, 82 with competence for germline and somatic lineage specification 17, 45, 81, 83. This process is asynchronous, with individual ES cells departing from the naïve state at different times 16, 84, 85. The findings here indicate that pERK1/2 activity is limiting for progression from the naïve state.…”

Section: Discussionmentioning

confidence: 99%

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

et al. 2018

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Mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) signalling is implicated in initiation of embryonic stem (ES) cell differentiation. The pathway is subject to complex feedback regulation. Here, we examined the ERK‐responsive phosphoproteome in ES cells and identified the negative regulator RSK1 as a prominent target. We used CRISPR/Cas9 to create combinatorial mutations in RSK family genes. Genotypes that included homozygous null mutations in Rps6ka1, encoding RSK1, resulted in elevated ERK phosphorylation. These RSK‐depleted ES cells exhibit altered kinetics of transition into differentiation, with accelerated downregulation of naïve pluripotency factors, precocious expression of transitional epiblast markers and early onset of lineage specification. We further show that chemical inhibition of RSK increases ERK phosphorylation and expedites ES cell transition without compromising multilineage potential. These findings demonstrate that the ERK activation profile influences the dynamics of pluripotency progression and highlight the role of signalling feedback in temporal control of cell state transitions.

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“…In this situation, BMP and Wnt/β-Catenin signalling in the context of low FGF/ERK signalling and high levels of E-Cadherin, play a pivotal role in this balance (Ying et al, 2003a; Ying et al, 2008; Wray et al, 2011; Faunes et al, 2013; Malaguti et al, 2013) and maintain the pluripotency network in a homeostatic steadiness. Triggering differentiation artificially and neutrally e.g.…”

Section: Discussionmentioning

confidence: 99%

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

et al. 2014

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Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a “race for fates” in which the neuroectodermal fate has an advantage.

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Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin

Cited by 69 publications

References 59 publications

The effect ofId1gene silencing on the neural differentiation of MSCs

The effect ofId1gene silencing on the neural differentiation of MSCs

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

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