Progesterone signaling/miR-200a/zeb2 axis regulates self-renewal of mouse embryonic stem cells

Progesterone is a steroid hormone and plays an important role during pregnancy. But the regulation mechanisms of progesterone-progesterone receptor (P4-PR) signaling during pregnancy remain largely unknown. In this study, we used medroxyprogesterone 17-acetate (MPA) which is a synthetic variant of progesterone and has 20–30 times the activity of progesterone to find that at the same physiological concentration as progesterone during early pregnancy MPA had no significant influence on ES cells self-renewal. But with the increasing of dosage, MPA can inhibit the self-renewal capacity of mouse embryonic stem cells (ES cells) and promote differentiation untimely. We further determined that MPA can influence the miR-200a/zeb2 pathway by down regulating the level of miR-200a. miR-200a significantly higher expressed in ES cells to down-regulate the expression of zeb2 to inhibit the self-renewal and promote differentiation of ES cells. Then we found that the function of MPA can be rescued by over-expression of miR-200a or down-regulation of zeb2. Our findings revealed the progesterone signaling/miR-200a/zeb2 axis regulating the progesterone signaling to insure the balance of self-renewal and differentiation of ES cells. Our study also provided new insight into the dosage of progesterone and it's derivant in the hormone replacement therapy for pregnant woman.