Abstract
The ETS transcription factor Etv2 is necessary and sufficient for the generation of hematopoietic and endothelial cells. However, upstream regulators of Etv2 in hemangiogenesis, generation of hematopoietic and endothelial cells, have not been clearly addressed. Here we track the developmental route of hemangiogenic progenitors from mouse embryonic stem cells, perform genome-wide CRISPR screening, and transcriptome analysis of en route cell populations by utilizing Brachyury, Etv2, or Scl reporter embryonic stem cell lines to further understand the mechanisms that control hemangiogenesis. We identify the forkhead transcription factor Foxh1, in part through Eomes, to be critical for the formation of FLK1+ mesoderm, from which the hemangiogenic fate is specified. Importantly, hemangiogenic fate is specified not simply by the onset of Etv2 expression, but by a threshold-dependent mechanism, in which VEGF-FLK1 signaling plays an instructive role by promoting Etv2 threshold expression. These studies reveal comprehensive cellular and molecular pathways governing the hemangiogenic cell lineage development.
Highlights
The ETS transcription factor Etv[2] is necessary and sufficient for the generation of hematopoietic and endothelial cells
Given that Etv[2] functions at the core of the genetic pathway in the generation of hemangiogenic progenitor cells[8,9,10], we reasoned that tracking its expression would help delineate molecular and cellular events leading to hemangiogenic cell lineage specification
Blast-colonyforming cells (BL-CFCs, representing hemangiogenic potential in vitro)[3, 15] were enriched in Etv2-tdTomatohigh cells, confirming that hemangiogenic fate is specified in Etv2-tdTomatohigh cells (Fig. 1b, right)
Summary
The ETS transcription factor Etv[2] is necessary and sufficient for the generation of hematopoietic and endothelial cells. Hemangiogenic fate is specified not by the onset of Etv[2] expression, but by a threshold-dependent mechanism, in which VEGF-FLK1 signaling plays an instructive role by promoting Etv[2] threshold expression These studies reveal comprehensive cellular and molecular pathways governing the hemangiogenic cell lineage development. It is crucial to generate a comprehensive lineage map, to identify extrinsic cues that guide a specific cell lineage outcome and to delineate downstream signal cascades and transcriptional networks involved in lineage specification Such information in turn would facilitate efforts deriving a desired cell type from pluripotent stem cells for regenerative medicine. Enforced Etv[2] expression can ectopically activate both cell lineages[8,9,10] These studies support the notion that Etv[2] functions at the core of the common genetic pathway in blood and endothelial cell generation. G Violin plots showing fold changes of RNA-seq RPKM values of 73 ETV2 target genes in populations 2, 3, and 4, respectively, compared to population 1
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