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.