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Keywords:

  • embryonic stem cell;
  • hemangioblast;
  • hematopoiesis;
  • LPA ;
  • zebrafish

Abstract

Primitive hematopoiesis occurs in the yolk sac blood islands during vertebrate embryogenesis, where abundant phosphatidylcholines (PC) are available as important nutrients for the developing embryo. However, whether these phospholipids also generate developmental cues to promote hematopoiesis is largely unknown. Here, we show that lysophosphatidic acid (LPA), a signaling molecule derived from PC, regulated hemangioblast formation and primitive hematopoiesis. Pharmacological and genetic blockage of LPA receptor 1 (LPAR1) or autotoxin (ATX), a secretory lysophospholipase that catalyzes LPA production, inhibited hematopoietic differentiation of mouse embryonic stem cells and impaired the formation of hemangioblasts. Mechanistic experiments revealed that the regulatory effect of ATX-LPA signaling was mediated by PI3K/Akt-Smad pathway. Furthermore, during in vivo embryogenesis in zebrafish, LPA functioned as a developmental cue for hemangioblast formation and primitive hematopoiesis. Taken together, we identified LPA as an important nutrient-derived developmental cue for primitive hematopoiesis as well as a novel mechanism of hemangioblast regulation.

Synopsis

Thumbnail image of graphical abstract

Yolk sac phosphatidylcholines serve not only nutrient roles for the developing embryo, but can also give rise to signaling molecules that are here shown to regulate hemangioblast formation and primitive hematopoiesis in vertebrates.

  • Pharmocological and genetic blockage of LPA signaling impairs hemangioblast formation and hematopoietic differentiation of mouse embryonic stem cells (mESCs).
  • LPA signaling regulates mESCs hematopoietic differentiation through activating PI3K/Akt-Smad pathway.
  • LPA signaling is required for hemangioblast formation and primitive hematopoiesis in zebrafish.