Pig Epiblast Stem Cells Depend on Activin/Nodal Signaling for Pluripotency and Self-Renewal

Alberio, Ramiro; Croxall, Nicola; Allegrucci, Cinzia

doi:10.1089/scd.2010.0012

Cited by 107 publications

(108 citation statements)

References 40 publications

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“…This delay in comparison with the mouse model may suggest that, from an epigenetic point of view, the mouse blastocyst is more advanced than the ungulate blastocyst, which, unlike the rodent embryo, is not ready to implant. In agreement with this observation, embryonic stem cell derivation attempts from bovine, sheep, or pig ICM cells have not succeeded, whereas epiblast stem cells have been derived in pigs (Alberio et al 2010). The reason for the incomplete inactivation of two genes (UBE2A and SAT1) is unclear.…”

Section: Discussionmentioning

confidence: 88%

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

Bermejo-Álvarez¹,

Rizos²,

Lonergan³

et al. 2011

Reproduction

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Sex chromosome transcripts can lead to a broad transcriptional sexual dimorphism in the absence of concomitant or previous exposure to sex hormones, especially when X-chromosome inactivation (XCI) is not complete. XCI timing has been suggested to differ greatly among species, and in bovine, most of the X-linked transcripts are upregulated in female blastocysts. To determine the timing of XCI, we analyzed in day 14 bovine embryos the sexual dimorphic transcription of seven X-linked genes known to be upregulated in female blastocysts (X24112, brain-expressed X-linked 2 (BEX2), ubiquitin-conjugating enzyme E2A (UBE2A), glucose-6-phosphate dehydrogenase (G6PD), brain-expressed X-linked 1 (BEX1), calpain 6 (CAPN6), and spermidine/spermine N-acetyltransferase 1 (SAT1)). The transcription of five genes whose expression differs between sexes at the blastocyst stage (DNMT3A, interferon tau (IFNT2), glutathione S-transferase mu 3 (GSTM3), progesterone receptor membrane component 1 (PGRMC1), and laminin alpha 1 (LAMA1)) and four genes related with sex determination (Wilms tumor 1 (WT1), gata binding protein 4 (GATA4), zinc finger protein multitype 2 (ZFPM2), and DMRT1) was also analyzed to determine the evolution of transcriptional sexual dimorphism. The expression level of five X-linked transcripts was effectively equalized among sexes suggesting that, in cattle, a substantial XCI occurs during the period between blastocyst hatching and initiation of elongation, although UBE2A and SAT1 displayed significant transcriptional differences. Similarly, sexual dimorphism was also reduced for autosomal genes with only DNMT3A and IFNT2 exhibiting sex-related differences. Among the genes potentially involved in sex determination, Wilms tumor 1 (WT1) was significantly upregulated in males and GATA4 in females, whereas no differences were observed for ZFPM2 and DMRT1. In conclusion, a major XCI occurred between the blastocyst and early elongation stages leading to a reduction in the transcriptional sexual dimorphism of autosomal genes, which makes the period the most susceptible to sex-specific embryo loss.

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Section: Discussionmentioning

confidence: 88%

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

Bermejo-Álvarez¹,

Rizos²,

Lonergan³

et al. 2011

Reproduction

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“…Activin/Nodal signaling is now well established in the maintenance of pluripotency of human and rabbit ES cells (Honda et al 2009;James et al 2005;Vallier et al 2004) and mouse and pig epiblast stem cells (EpiSC), which are derived from the epiblast of post-implantation, pre-gastrula embryos (Alberio et al 2010;Brons et al 2007;Tesar et al 2007). EpiSCs, like human and rabbit ES cells, require the presence of FGF2 and Activin in order to maintain pluripotency (Brons et al 2007;Chou et al 2008;Tesar et al 2007).…”

Section: Implications For Embryonic Stem (Es) and Embryonic Germ (Eg)mentioning

confidence: 99%

Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors

Spiller

Bowles²,

Koopman

2013

Int. J. Dev. Biol.

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Testicular cancer is the most frequent cancer in young men aged 15-40 years and accounts for 1% of all cancer diagnosed in males. Testicular germ cell tumors (TGCT) encompass a broad group of cancers, each displaying different levels of pluripotency and differentiation as well as malignancy potential. The TGCT cell of origin is thought to be a fetal germ cell that failed to correctly differentiate during development: this is known as the 'fetal origins hypothesis' . This theory predicts that developmental pathways that control germ cell pluripotency or differentiation may be involved in the malignant transformation of these cells. Recently the Nodal/Cripto signaling pathway, known to control pluripotency and differentiation in embryonic stem (ES) cells, was implicated in regulating normal male fetal germ cell pluripotency. Although genes of this pathway are not normally expressed in germ cells during adult life, ectopic expression of this pathway was detected in several sub-groups of TGCTs. In this review, we consider the evidence for the fetal origins of TGCT and discuss the implications of Nodal/Cripto signaling in various aspects of germ cell development and cancer progression.

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“…Nonetheless, in some instances, porcine lines have shown some measure of stemness, including an ability to be maintained in culture for prolonged periods (Evans et al, 1990), to form teratomas, and, in one instance, to give rise to chimeras (Chen et al, 1999). Recently, however, porcine cell lines have been generated from the embryonic disc of d 10.5-12 pig conceptuses that were dependent on ACTIVIN/NODAL signaling but not on LIF, differentiated into trophoblast and germ cells upon BMP4 treatment, and could give rise to teratomas (Alberio et al, 2010). These cell lines, like those from human blastocysts, clearly fall into the primed ESC class and their existence underscores the commonality of the FGF2-dependent pluripotent state across very different species.…”

Section: Pluripotent Stem Cells From Pigmentioning

confidence: 99%

Porcine induced pluripotent stem cells analogous to nave and primed embryonic stem cells of the mouse

Telugu¹,

Ezashi²,

Roberts³

2010

Int. J. Dev. Biol.

104

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Authentic or naïve embryonic stem cells (ESC) have probably never been derived from the inner cell mass (ICM) of pig blastocysts, despite over 25 years of effort. Recently, several groups, including ours, have reported induced pluripotent stem cells (iPSC) from swine by reprogramming somatic cells with a combination of four factors, OCT4 (POU5F1)/SOX2/KLF4/c-MYC delivered by retroviral transduction. The porcine (p) iPSC resembled human (h) ESC and the mouse "Epiblast stem cells" (EpiSC) in their colony morphology and expression of pluripotent genes, and are likely dependent on FGF2/ACTIVIN/NODAL signaling, therefore representing a primed ESC state. These cells are likely to advance swine as a model in biomedical research, since grafts could potentially be matched to the animal that donated the cells for re-programming. The objective of the present work has been to develop naïve piPSC. Employing a combination of seven reprogramming factors assembled on episomal vectors, we successfully reprogrammed porcine embryonic fibroblasts on a modified LIF-medium supplemented with two kinase inhibitors; CHIR99021, which inhibits GSK-3beta, and PD0325901, a MEK inhibitor. The derived piPSC bear a striking resemblance to naïve mESC in colony morphology, are dependent on LIF to maintain an undifferentiated phenotype, and express markers consistent with pluripotency. They exhibit high telomerase activity, a short cell cycle interval, and a normal karyotype, and are able to generate teratomas. Currently, the competence of these lines for contributing to germ-line chimeras is being tested. KEY WORDS: pig, naïve, primed, induced pluripotent stem cell, embryonic stem cellNaïve and primed embryonic stem cells Authentic or "naïve" embryonic stem cells (ESC) (Nichols and Smith, 2009), the pluripotent stem cell lines derived from the inner cell mass (ICM) of the embryo, were first established from certain strains of d 3.5 mouse (m) embryos over 30 years ago (Evans and Kaufman, 1981;Martin, 1981). Such established mESC lines are characterized by their dependence on LIF/STAT3 signaling for maintenance of pluripotency (Hall et al., 2009), the positive effects of BMP4 for self renewal and resistance to differentiation (Ying et al., 2003), and tendency to differentiate in response to activation of the FGF2 and ACTIVIN/TGFB signal transduction pathways . Naïve ESC are also tolerant to passaging as single cells, show no signs of either senescence over extended culture doublings and, in female lines, of X chromosome inactivation. As they are pluripotent, mESC have the ability to differentiate into cell types representing the three main germ layers (ectoderm, mesoderm, and endoderm) both in vitro and in Int. J. Dev. Biol. 54: 1703-1711 (2010) vivo, and to give rise to germ-line chimeras and even the whole animal after being introduced into pre-implantation embryos (Evans, 2005;Wobus and Boheler, 2005). This latter attribute, which has allowed genes to be ablated or added ("knock-outs" and "knock-ins", respectively) to the genome h...

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Pig Epiblast Stem Cells Depend on Activin/Nodal Signaling for Pluripotency and Self-Renewal

Cited by 107 publications

References 40 publications

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors

Porcine induced pluripotent stem cells analogous to nave and primed embryonic stem cells of the mouse

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