title: PDGFRα+Cells in Embryonic Stem Cell Cultures Represent the In Vitro Equivalent of the Pre-implantation Primitive Endoderm Precursors.
abstract: 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.
authors.affiliation: 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; 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. Electronic address: antoniolonigro83@gmail.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lo Nigro
authors.affiliation: 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.
authors.forename: Anchel
authors.initials: A
authors.lastname: de Jaime-Soguero
authors.affiliation: 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.
authors.forename: Rita
authors.initials: R
authors.lastname: Khoueiry
authors.affiliation: Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Avenue Southeast, Minneapolis, MN 55455, USA.
authors.forename: Dong Seong
authors.initials: DS
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Giorgia Maria
authors.initials: GM
authors.lastname: Ferlazzo
authors.affiliation: 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.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Perini
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium; KU Leuven Department of Human Genetics, 3000 Leuven, Belgium.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Abon Escalona
authors.affiliation: Cell Therapy Program, Foundation for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Xabier Lopez
authors.initials: XL
authors.lastname: Aranguren
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Chuva de Sousa Lopes
authors.affiliation: 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.
authors.forename: Kian Peng
authors.initials: KP
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Pier Giulio
authors.initials: PG
authors.lastname: Conaldi
authors.affiliation: Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Avenue Southeast, Minneapolis, MN 55455, USA.
authors.forename: Wei-Shou
authors.initials: WS
authors.lastname: Hu
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium; KU Leuven Department of Human Genetics, 3000 Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.affiliation: 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.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lluis
authors.affiliation: 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.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
mesh_terms: D042683:Angiopoietin-1; D000818:Animals; D015415:Biomarkers; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D019175:DNA Methylation; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D015415:Biomarkers; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: PDGFRα+ subpopulations; embryonic stem cell heterogeneity; in vitro model of early blastocyst development; pre-implantation PrE precursors