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

Antonio Lo Nigro, Anchel de Jaime-Soguero, Rita Khoueiry, Dong Seong Cho, Giorgia Maria Ferlazzo, Ilaria Perini, Vanesa Abon Escalona, Xabier Lopez Aranguren, Susana M Chuva de Sousa Lopes, Kian Peng Koh, Pier Giulio Conaldi, Wei-Shou Hu, An Zwijsen, Frederic Lluis, Catherine M Verfaillie

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)318-333
Number of pages16
JournalStem Cell Reports
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 14 2017

Keywords

  • Angiopoietin-1
  • Animals
  • Biomarkers
  • Blastocyst
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • DNA Methylation
  • Embryonic Development
  • Embryonic Stem Cells
  • Endoderm
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental
  • Mice
  • Receptor, Platelet-Derived Growth Factor alpha
  • Signal Transduction
  • Journal Article
  • Research Support, Non-U.S. Gov't

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