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      Human hypoblast formation is not dependent on FGF signalling

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          Abstract

          Mouse embryos segregate three different lineages during preimplantation development: trophoblast, epiblast and hypoblast. These differentiation processes are associated with restricted expression of key transcription factors (Cdx2, Oct4, Nanog and Gata6). The mechanisms of segregation have been extensively studied in the mouse, but are not as well characterised in other species. In the human embryo, hypoblast differentiation has not previously been characterised. Here we demonstrate co-exclusive immunolocalisation of Nanog and Gata4 in human blastocysts, implying segregation of epiblast and hypoblast, as in rodent embryos. However, the formation of hypoblast in the human is apparently not dependent upon FGF signalling, in contrast to rodent embryos. Nonetheless, the persistence of Nanog-positive cells in embryos following treatment with FGF inhibitors is suggestive of a transient naïve pluripotent population in the human blastocyst, which may be similar to rodent epiblast and ES cells but is not sustained during conventional human ES cell derivation protocols.

          Highlights

          ► Segregation of epiblast and Gata4-positive hypoblast in human blastocysts ► Insensitivity of human hypoblast formation to FGF/Erk inhibition ► Persistence of Nanog-positive cells in human epiblast after FGF/Erk inhibition

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          Naive and primed pluripotent states.

          Jennifer Nichols, Austin Smith (2009)
          After maternal predetermination gives way to zygotic regulation, a ground state is established within the mammalian embryo. This tabula rasa for embryogenesis is present only transiently in the preimplantation epiblast. Here, we consider how unrestricted cells are first generated and then prepared for lineage commitment. We propose that two phases of pluripotency can be defined: naive and primed. This distinction extends to pluripotent stem cells derived from embryos or by molecular reprogramming ex vivo.
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            Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway.

            Claire Chazaud, Yojiro Yamanaka, Tony Pawson … (2006)
            It has been thought that early inner cell mass (ICM) is a homogeneous population and that cell position in the ICM leads to the formation of two lineages, epiblast (EPI) and primitive endoderm (PE), by E4.5. Here, however, we show that the ICM at E3.5 is already heterogeneous. The EPI- and PE-specific transcription factors, Nanog and Gata6, were expressed in the ICM in a random "salt and pepper" pattern, as early as E3.5, in a mutually exclusive manner. Lineage tracing showed predominant lineage restriction of single ICM cells at E3.5 to either lineage. In embryos lacking Grb2 where no PE forms, Gata6 expression was lost and all ICM cells were Nanog positive. We propose a model in which the ICM develops as a mosaic of EPI and PE progenitors at E3.5, dependent on Grb2-Ras-MAP kinase signaling, followed by later segregation of the progenitors into the appropriate cell layers.
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              Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs.

              Jacob A. Hanna, Albert W Cheng, Krishanu Saha … (2010)
              Human and mouse embryonic stem cells (ESCs) are derived from blastocyst-stage embryos but have very different biological properties, and molecular analyses suggest that the pluripotent state of human ESCs isolated so far corresponds to that of mouse-derived epiblast stem cells (EpiSCs). Here we rewire the identity of conventional human ESCs into a more immature state that extensively shares defining features with pluripotent mouse ESCs. This was achieved by ectopic induction of Oct4, Klf4, and Klf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3beta (GSK3beta) and mitogen-activated protein kinase (ERK1/2) pathway. Forskolin, a protein kinase A pathway agonist which can induce Klf4 and Klf2 expression, transiently substitutes for the requirement for ectopic transgene expression. In contrast to conventional human ESCs, these epigenetically converted cells have growth properties, an X-chromosome activation state (XaXa), a gene expression profile, and a signaling pathway dependence that are highly similar to those of mouse ESCs. Finally, the same growth conditions allow the derivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. The generation of validated "naïve" human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans and may open up new opportunities for patient-specific, disease-relevant research.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Dev Biol
                Journal ID (iso-abbrev): Dev. Biol
                Title: Developmental Biology
                Publisher: Elsevier
                ISSN (Print): 0012-1606
                ISSN (Electronic): 1095-564X
                Publication date PMC-release: 15 January 2012
                Publication date (Print): 15 January 2012
                Volume: 361
                Issue: 2-6
                Pages: 358-363
                Affiliations
                [a ]Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
                [b ]Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
                [c ]Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
                [d ]Bourn Hall Clinic, Bourn, Cambridge CB23 2TN, UK
                [e ]Centre for Reproductive Medicine, Barts and The London, West Smithfield, London EC1A 7BE, UK
                Author notes
                [* ]Corresponding author at: Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK. Fax: + 44 1223 760241. jn270@ 123456cam.ac.uk
                Article
                Publisher ID: YDBIO5512
                DOI: 10.1016/j.ydbio.2011.10.030
                PMC ID: 3368271
                PubMed ID: 22079695
                SO-VID: 9173503f-97fc-4d43-baf6-ebe3c95655ab
                Copyright © © 2012 Elsevier Inc.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 24 August 2011
                Date revision received : 24 October 2011
                Date accepted : 26 October 2011
                Categories
                Subject: Article

                ScienceOpen disciplines: Developmental biology
                Keywords: hypoblast,fibroblast growth factor,epiblast,pluripotency,human es cell derivation
                Data availability:
                ScienceOpen disciplines: Developmental biology
                Keywords: hypoblast, fibroblast growth factor, epiblast, pluripotency, human es cell derivation

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