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

In recent decades, study of the actions of bioactive lipids such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) has increased since they are involved in regulating many processes, including self-renewal of embryonic stem cells, embryo development and cancer. Phospholipid phosphatase type 3 (PLPP3) has been shown to be a key player in regulating the balance of these lipids and, in consequence, their signaling. Different lines of evidence suggest that PLPP3 could play a role in endoderm development. To approach this hypothesis, we used 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 differentiation of suspension-formed embryoid bodies. PLPP3-deficient ESC strongly decrease 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.

Automated summary

In recent decades, the study of bioactive lipids such as LPA and S1P has increased due to their involvement in regulating various processes. PLPP3 has been identified as a key player in maintaining the balance of these lipids and their signaling, and it may also play a role in endoderm development. This study used mouse ESCs to investigate the function of PLPP3 in self-renewal and differentiation, and found that PLPP3 deficiency primarily affected endoderm formation. Impaired endoderm differentiation was associated with decreased YAP1 nuclear localization, and these phenotypes were rescued by restoring the expression of catalytically active hPLPP3.