Modulation of Aplnr signaling is required during the development and maintenance of the hematopoietic system

Abstract

Apelin receptor (Aplnr/Agtrl1/Apj) marks a transient cell population during the differentiation of hematopoietic progenitor cells (HPCs) from pluripotent stem cells but the function of this signalling pathway during hematopoietic development both in vitro and in vitro is poorly understood. We generated an Aplnr-null mouse embryonic stem cell (mESC) line and demonstrated that they are significantly impaired in the production of HPCs indicating that the Aplnr pathway is required for their formation. Using Aplnr-tdTomato reporter mESCs we demonstrated that is expressed in a population of differentiating mesodermal cells committed to a hematopoietic and endothelial fate. Activation of this signaling pathway by the addition of the Apelin ligand to differentiating ESCs has no effect on the production of HPCs but the addition to ex vivo AGM cultures impaired the generation of long term reconstituting hematopoietic stem cells and appeared to drive myeloid differentiation. Taken together, our data suggest that the Aplnr pathway is required for the generation of cells that give rise to HSCs during development but its subsequent down regulation is required for their maintenance. HIGHLIGHTSO_LIHematopoietic differentiation is impaired in Aplnr-null ESCs C_LIO_LIAplnr-tdTomato reporter marks a subpopulation of ESC-derived mesoderm. C_LIO_LIAplnr signaling drives the maturation of lineage-committed myeloid progenitors C_LIO_LIIn AGM explant cultures HSC activity is reduced in the presence of Aplnr ligands. C_LI