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      PDGFRα + Cells in Embryonic Stem Cell Cultures Represent the In Vitro Equivalent of the Pre-implantation Primitive Endoderm Precursors


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          In early mouse pre-implantation development, primitive endoderm (PrE) precursors are platelet-derived growth factor receptor alpha (PDGFRα) positive. Here, we demonstrated that cultured mouse embryonic stem cells (mESCs) express PDGFRα heterogeneously, fluctuating between a PDGFRα+ (PrE-primed) and a platelet endothelial cell adhesion molecule 1 (PECAM1)-positive state (epiblast-primed). The two surface markers can be co-detected on a third subpopulation, expressing epiblast and PrE determinants (double-positive). In vitro, these subpopulations differ in their self-renewal and differentiation capability, transcriptional and epigenetic states. In vivo, double-positive cells contributed to epiblast and PrE, while PrE-primed cells exclusively contributed to PrE derivatives. The transcriptome of PDGFRα + subpopulations differs from previously described subpopulations and shows similarities with early/mid blastocyst cells. The heterogeneity did not depend on PDGFRα but on leukemia inhibitory factor and fibroblast growth factor signaling and DNA methylation. Thus, PDGFRα + cells represent the in vitro counterpart of in vivo PrE precursors, and their selection from cultured mESCs yields pure PrE precursors.

          Graphical Abstract


          • Three subpopulations can be purified from mESC cultures by using PECAM1 and PDGFRα

          • Expression of PDGFRα is associated with a molecular and epigenetic PrE signature

          • PDGFRα + cells are committed toward PrE derivatives in vitro and in vivo


          In this article, Lo Nigro and colleagues further dissect the heterogeneity of mESC cultures by using the endogenous and heterogeneous expression of PECAM1 and PDGFRα. By combining the expression of these surface markers, the authors describe a strategy to sort out a subpopulation that exclusively gives rise to extraembryonic endodermal derivatives in vitro and in vivo.

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          Most cited references33

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          Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

          G Martin (1981)
          This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.
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            Establishment in culture of pluripotential cells from mouse embryos.

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              Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture.

              Mouse embryonic stem (ES) cells are competent for production of all fetal and adult cell types. However, the utility of ES cells as a developmental model or as a source of defined cell populations for pharmaceutical screening or transplantation is compromised because their differentiation in vitro is poorly controlled. Specification of primary lineages is not understood and consequently differentiation protocols are empirical, yielding variable and heterogeneous outcomes. Here we report that neither multicellular aggregation nor coculture is necessary for ES cells to commit efficiently to a neural fate. In adherent monoculture, elimination of inductive signals for alternative fates is sufficient for ES cells to develop into neural precursors. This process is not a simple default pathway, however, but requires autocrine fibroblast growth factor (FGF). Using flow cytometry quantitation and recording of individual colonies, we establish that the bulk of ES cells undergo neural conversion. The neural precursors can be purified to homogeneity by fluorescence activated cell sorting (FACS) or drug selection. This system provides a platform for defining the molecular machinery of neural commitment and optimizing the efficiency of neuronal and glial cell production from pluripotent mammalian stem cells.

                Author and article information

                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                12 January 2017
                14 February 2017
                12 January 2017
                : 8
                : 2
                : 318-333
                [1 ]Department of Development and Regeneration, Stem Cell Biology and Embryology, KU Leuven Stem Cell Institute, Herestraat 49, Onderwijs en Navorsing 4, Box 804, 3000 Leuven, Belgium
                [2 ]Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Avenue Southeast, Minneapolis, MN 55455, USA
                [3 ]VIB Center for the Biology of Disease, 3000 Leuven, Belgium
                [4 ]KU Leuven Department of Human Genetics, 3000 Leuven, Belgium
                [5 ]Cell Therapy Program, Foundation for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
                [6 ]Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands
                [7 ]Ri.Med Foundation, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via Tricomi 5, 90127 Palermo, Italy
                Author notes
                []Corresponding author antoniolonigro83@ 123456gmail.com

                Co-first author


                Co-senior author

                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 22 October 2015
                : 9 December 2016
                : 12 December 2016

                embryonic stem cell heterogeneity,pre-implantation pre precursors,in vitro model of early blastocyst development,pdgfrα+ subpopulations


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