Plpp3, a novel regulator of pluripotency exit and endodermal differentiation of mouse embryonic stem cells.

In recent decades the study of the actions of bioactive lipids such as Lysophosphatidic Acid (LPA) and Sphingosine-1-Phosphate (S1P) has importantly increased since they are involved in regulating many processes, including self-renewal of embryonic stem cells, embryo development and cancer. The Phospholipid Phosphatase type 3 (PLPP3) has been shown key player in regulating the balance of these lipids, and in consequence their signaling. Different lines of evidence suggest PLPP3 could play a role in endoderm development, to approach this hypothesis we use mouse embryonic stem cells (ESC) as a model to study Plpp3 function in self-renewal and the transition towards differentiation. We found that lack of PLPP3 mainly affects endoderm formation during suspension embryoid bodies differentiation. PLPP3-deficient ESC strongly decreases the amount of FOXA2 expressing cells and fail to properly downregulate the expression of pluripotency factors when subjected to an endoderm directed differentiation protocol. Impaired endoderm differentiation correlated with a transient reduction in nuclear localization of YAP1. These phenotypes were rescued by transiently restoring the expression of catalytically active hPLPP3. In conclusion, PLPP3 plays a role in downregulating pluripotency-associated factors and in endodermal differentiation. PLPP3 regulates proper lipid/YAP1 signaling required for endodermal differentiation.