PDGF Receptor Alpha+ Mesoderm Contributes to Endothelial and Hematopoietic Cells in Mice

Abstract

Background: Early mesoderm can be classified into Flk-1+ or PDGF receptor alpha (PDGFRα)+ population, grossly representing lateral and paraxial mesoderm, respectively. It has been demonstrated that all endothelial (EC) and hematopoietic (HPC) cells are derived from Flk-1+ cells. Although PDGFRα+ cells give rise to ECs/HPCs in in vitro ES differentiation, whether PDGFRα+ population can become hemato-endothelial lineages has not been proved in mouse embryos. Results: Using PDGFRαMerCreMer mice, PDGFRα+ early mesoderm was shown to contribute to endothelial cells including hemogenic ECs, fetal liver B lymphocytes, and Lin-Kit+Sca-1+ (KSL) cells. Contribution of PDGFRα+ mesoderm into ECs and HPCs was limited until E8.5, indicating that PDGFRα+/Flk-1+ population that exists until E8.5 may be the source for hemato-endothelial lineages from PDGFRα+ population. The functional significance of PDGFRα+ mesoderm in vascular development and hematopoiesis was confirmed by genetic deletion of Etv2 or restoration of Runx1 in PDGFRα+ cells. Etv2 deletion and Runx1 restoration in PDGFRα+ cells resulted in abnormal vascular remodeling and rescue of fetal liver CD45+ and Lin-Kit+Sca-1+ (KSL) cells, respectively. Conclusions: Endothelial and hematopoietic cells can be derived from PDGFRα+ early mesoderm in mice. PDGFRα+ mesoderm is functionally significant in vascular development and hematopoiesis from phenotype analysis of genetically modified embryos. Developmental Dynamics 242:254–268, 2013. © 2013 Wiley Periodicals, Inc.Key FindingsPDGF receptor alpha–positive mesoderm contributes to endothelial and hematopoietic cells in physiological mouse embryogenesis.PDGF receptor alpha–positive mesoderm in early embryo is distinct from yolk sac blood island mesoderm, representing a source of hematopoietic cells on the embryo proper side.Genetic manipulation of Etv2 or Runx1 in PDGF receptor alpha–positive mesoderm demonstrates the functional significance of this mesoderm subset in vascular development and hematopoiesis.

The Etv2-miR-130a Network Regulates Mesodermal Specification

“…However, these results are supported by the finding that fetal liver hematopoiesis was not affected in the Pdgfra conditional knockout embryos (Ding et al, 2013). Our data together with others (Ding et al, 2013) support the notion that the endothelial, but not the hematopoietic lineage is sensitive to the level of Pdgfra.…”

“…However, these results are supported by the finding that fetal liver hematopoiesis was not affected in the Pdgfra conditional knockout embryos (Ding et al, 2013). Our data together with others (Ding et al, 2013) support the notion that the endothelial, but not the hematopoietic lineage is sensitive to the level of Pdgfra. We propose that as Flk1 + /Pdgfra + common mesodermal progenitors progress to the Flk1 + /Pdgfra − hemato-endothelial progenitors, miR-130a further down-regulates Pdgfra expression to direct cells towards the endothelial lineage (Figure S4).…”

The many faces of hematopoietic stem cell heterogeneity

“…This hemogenic competence of endothelial progenitors was further shown to be restricted by Runx1 silencing (Eliades et al, 2016). Interestingly, a subset of endothelial cells and hematopoietic cells located ventrally in the E10.5 AGM and a subset of endothelial cells and hematopoietic progenitor/stem cells in the E15.5 fetal liver can be derived from PDGFRα + early paraxial mesodermal cells, as shown by cell tracing in which PDGFRα + cells were labelled at E7.5-E8 by tamoxifen injections into pregnant females (Ding et al, 2013). However, PDGFRα is dispensable for the development of fetal liver hematopoiesis and P dgfra- deleted mice die from a cephalic closure defect and skeletal abnormalities (Soriano, 1997).…”

Making muscle: skeletal myogenesisin vivoandin vitro

“…However, the usefulness of these markers is limited by their overall poor lineage specificity. Notably, PDGFRα and VEGFR2 are dynamically expressed on several mesodermal populations including paraxial mesoderm and lateral plate mesoderm and thus are not lineage-specific markers (Ding et al, 2013;Ema et al, 2006;Motoike et al, 2003;Takebe et al, 2006). Fluorescent reporters.…”