Capturing the ephemeral human pluripotent state

Ávila-González, Daniela; García‐López, Guadalupe; García-Castro, Irma Lydia; Flores‐Herrera, Héctor; Molina‐Hernández, Anayansí; Portillo, Wendy; Díaz, Néstor Fabián

doi:10.1002/dvdy.24405

Cited by 10 publications

(12 citation statements)

References 101 publications

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“…That NODAL transcript levels were dramatically and reversibly influenced by culture conditions may be an indication that more general differences exist between hES cells cultured in MEF-conditioned serum replacementbased media and in more defined media. In general, some differences in hES cells cultured under varying conditions have been observed 70,71 . However, very little work has directly compared culture of hES cells in MEF-CM to culture in defined media such as mTESR 72 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of transcript diversity at the humanNODALlocus

Postovit

2018

Preprint

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NODAL, a morphogen belonging to the transforming growth factor beta (TGFb) superfamily, is essential during embryogenesis where it induces axis formation and left-right asymmetry. NODAL is also required for the maintenance of human embryonic stem cell pluripotency, and emerges in many cancer types concomitant with metastasis and therapy resistance. Several enhancer elements have been shown to regulate mouse Nodal expression and studies have delineated mechanisms by which mRNA splicing and translation of NODAL homologues are regulated in model organisms.However, little is known regarding the co-transcriptional and post-transcriptional processing of human NODAL. Herein, we describe hitherto unreported RNAs which are transcribed from the NODAL locus, including an antisense transcript, a circular transcript, and multiple splice variants.These transcripts demonstrate the complexity of NODAL expression and highlight the need to consider each NODAL variant when attempting to quantify or target this morphogen. Introduction:The transforming growth factor-beta (TGF-β) superfamily member nodal growth differentiation factor (human gene symbol: NODAL, NCBI gene ID: 4838) plays essential roles in early embryonic development and is reactivated in cancers. Nodal is aptly named after its discovery in the mouse node in gastrula-stage embryos 1 . Nodal has been well studied in numerous vertebrate embryos and in vitro models of early development 2-5 . These studies have shown that Nodal promotes epiblast expansion and maintenance in blastocyst stage embryos 6 , directs the specification of the distal visceral endoderm (DVE) after implantation 7 , establishes the proximaldistal 8 and anterior-posterior 8,9 axes, influences mesendoderm differentiation during gastrulation (reviewed in 5 ), and establishes left-right asymmetry 10 11-13 .Owing to practical and ethical limitations concerning research on human embryos, human-specific study of NODAL biology has generally been limited to cultured human embryonic stem (hES) cells where NODAL helps maintain pluripotency 14 , and blocks differentiation toward neuroectoderm lineages 15 . In addition, active SMAD2/3 downstream of NODAL (and other TGF-βs) also mediates cell fate decisions during mesendoderm differentiation [16][17][18][19] .NODAL expression in cancer was first identified by Postovit and Topczewska and colleagues in the aggressive C8161 human melanoma cell line 20 . These cells were able to induce ectopic outgrowths or a complete secondary axis after injection into zebrafish embryos at the blastocyst

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Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of transcript diversity at the humanNODALlocus

Postovit

2018

Preprint

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“…A recent flurry of reports described the derivation of so-called naïve pluripotent human ESCs (Chan et al, 2013; Chen et al, 2015a,b; Duggal et al, 2015; Gafni et al, 2013; Takashima et al, 2014; Theunissen et al, 2014; Valamehr et al, 2014; Ware et al, 2014; reviewed by Ávila-González et al, 2016). All of these conditions are modifications of the 2i/LIF culture regime developed for efficient mouse ESC derivation and culture.…”

Section: Capturing Pluripotent States From the Embryomentioning

confidence: 99%

Primate embryogenesis predicts the hallmarks of human naïve pluripotency

2017

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Naïve pluripotent mouse embryonic stem cells (ESCs) resemble the preimplantation epiblast and efficiently contribute to chimaeras. Primate ESCs correspond to the postimplantation embryo and fail to resume development in chimaeric assays. Recent data suggest that human ESCs can be ‘reset’ to an earlier developmental stage, but their functional capacity remains ill defined. Here, we discuss how the naïve state is inherently linked to preimplantation epiblast identity in the embryo. We hypothesise that distinctive features of primate development provide stringent criteria to evaluate naïve pluripotency in human and other primate cells. Based on our hypothesis, we define 12 key hallmarks of naïve pluripotency, five of which are specific to primates. These hallmarks may serve as a functional framework to assess human naïve ESCs.

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“…The developmental potency of in vitro established human cell lines isolated from preimplantation stage human embryos has been studied intensively over the past several years. The earliest developmental stage of human embryonic stem cells (hESCs) isolated in vitro are referred to as “naïve” (meaning of greater developmental potential) and subsequently transitions through to a stage of lesser potential termed “primed” (reviewed in Nichols and Smith, 2009; Davidson et al, 2015; Ávila-González et al, 2016; Hockemeyer and Jaenisch, 2016; Weinberger et al, 2016; Wu et al, 2016 and references therein). Cells of the primed stage are equivalent to epiblast cells of the preimplantation human embryo.…”

Section: Pluripotencymentioning

confidence: 99%

Implications for a Stem Cell Regenerative Medicine Based Approach to Human Intervertebral Disk Degeneration

Kraus

Lufkin

2017

Front. Cell Dev. Biol.

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The human body develops from a single cell, the zygote, the product of the maternal oocyte and the paternal spermatozoon. That 1-cell zygote embryo will divide and eventually grow into an adult human which is comprised of ~3.7 × 1013 cells. The tens of trillions of cells in the adult human can be classified into approximately 200 different highly specialized cell types that make up all of the different tissues and organs of the human body. Regenerative medicine aims to replace or restore dysfunctional cells, tissues and organs with fully functional ones. One area receiving attention is regeneration of the intervertebral discs (IVDs), which are located between the vertebrae and function to give flexibility and support load to the spine. Degenerated discs are a major cause of lower back pain. Different stem cell based regenerative medicine approaches to cure disc degeneration are now available, including using autologous mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs) and even attempts at direct transdifferentiation of somatic cells. Here we discuss some of the recent advances, successes, drawbacks, and the failures of the above-mentioned approaches.

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Capturing the ephemeral human pluripotent state

Cited by 10 publications

References 101 publications

Comprehensive characterization of transcript diversity at the humanNODALlocus

Comprehensive characterization of transcript diversity at the humanNODALlocus

Primate embryogenesis predicts the hallmarks of human naïve pluripotency

Implications for a Stem Cell Regenerative Medicine Based Approach to Human Intervertebral Disk Degeneration

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