TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency

Sierra, Robert A.; Hoverter, Nathan P.; Ramirez, Ricardo N.; Vuong, Linh; Mortazavi, A; Merrill, Bradley J.; Waterman, Marian L.; Donovan, Peter

doi:10.1242/dev.161075

Cited by 22 publications

(20 citation statements)

References 49 publications

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“…Most relevantly, significant interspecies differences in TCF3 and its target genes exist. For example, a recent study showed that TCF3 targets overlap less with those of the pluripotency regulators OCT4 and NANOG in hESCs than in mESCs and that human TCF3 acts generally on differentiation-specific rather than pluripotency-specific genes (Sierra et al 2018). In addition, while we found that mutually exclusive AS of TCF3 switches exon 18a (E12) to exon 18b (E47) during hESC differentiation, Salomonis et al (2010) reported that skipping of exon 4, which creates a short TCF3 isoform, is an mESC-specific AS event not conserved in hESCs even though the mESC-specific TCF3 isoform does regulate pluripotency and expression of early developmental genes.…”

Section: Rna-seqmentioning

confidence: 99%

TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency

et al. 2018

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Alternative splicing (AS) plays important roles in embryonic stem cell (ESC) differentiation. In this study, we first identified transcripts that display specific AS patterns in pluripotent human ESCs (hESCs) relative to differentiated cells. One of these encodes T-cell factor 3 (TCF3), a transcription factor that plays important roles in ESC differentiation. AS creates two TCF3 isoforms, E12 and E47, and we identified two related splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 and F (hnRNP H/F), that regulate TCF3 splicing. We found that hnRNP H/F levels are high in hESCs, leading to high E12 expression, but decrease during differentiation, switching splicing to produce elevated E47 levels. Importantly, hnRNP H/F knockdown not only recapitulated the switch in TCF3 AS but also destabilized hESC colonies and induced differentiation. Providing an explanation for this, we show that expression of known TCF3 target E-cadherin, critical for maintaining ESC pluripotency, is repressed by E47 but not by E12.

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Section: Rna-seqmentioning

confidence: 99%

TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency

et al. 2018

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“…Stem cells can be categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), fetal stem cells (FSCs), perinatal stem cells (PSCs), and adult stem cells (ASCs) [126]. ESCs are pluripotent stem cells isolated from the inner cell mass of blastocysts before the stage of gastrulation [127,128]. They have advantages for self-renewal and differentiation even if the formation of in vivo teratomas is a problematic point.…”

Section: Mesenchymal Stem Cells Potential In Neuronal Differentiationmentioning

confidence: 99%

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

Angeloni

Gatti

Prata

et al. 2020

IJMS

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Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.

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“…has been shown to be essential for self-renewal in mouse ESCs [79], TCF7L1 plays an important role in human ESC pluripotency via suppression of primitive streak gene expression [80].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds

McKee

Brown

Bakshi

et al. 2020

Preprint

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Derivation of primed and naïve human embryonic stem cells (ESCs) have prompted an increased interest in devising culture conditions for maintaining their pluripotency and differential potential. Naïve ESCs are characterized by improved viability, proliferation, and differentiation capacity in comparison to primed ESCs. However, traditional two-dimensional (2-D) cell culture techniques fail to mimic the three-dimensional (3-D) in vivo microenvironment, which results in altered morphological and molecular characteristics of ESCs. Here, we describe the use of 3-D self-assembling scaffolds that support growth and maintenance of the naïve state characteristics of human ESC line, Elf1. Scaffolds were formed via a Michael addition reaction upon combination of two 8-arm polyethylene glycol (PEG) polymers functionalized with thiol (PEG-8-SH) and acrylate (PEG-8-Acr) end groups. 3-D scaffolds not only maintained the naïve state, but also supported long-term growth for up to 3 weeks without requiring routine passaging and manipulation. 3-D grown cells exhibited upregulation of core (OCT4, NANOG, and SOX2) and naïve (KLF17, KLF4, TFCP2L1, DPPA3, and DNMT3L) genes. These genes returned to normal levels when 3-D grown cells were propagated under 2-D culture conditions. Examination of RNA-sequencing demonstrated significant changes in gene expression profiles between 2-D and 3-D grown Elf1 cells. Gene Ontology analysis revealed upregulation of biological processes involved in the regulation of transcription and translation, as well as β-catenin-TCF complex assembly, extracellular matrix organization, and chromatin remodeling in 3-D grown Elf1 cells. 3-D culture conditions also induced upregulation of genes associated with several signaling pathways including Wnt signaling and focal adhesion. However, p53 signaling pathway associated genes were downregulated under these culture conditions. Our findings provide insight into the possible mechanisms of prolonged self-renewal as well as upregulation of pluripotent genes stimulated by the transduction of mechanical signals from the 3-D microenvironment.

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TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency

Cited by 22 publications

References 49 publications

TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency

TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds

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