Role of decorin at the fetal-maternal interface
Abstract
The human placenta is an invasive tumor-like structure, this invasion being physiological. A subset of placental trophoblast called extra-villous trophoblast invades the uterine decidua and remodels uterine arteries into low-resistance, high-flow tubes to permit adequate flow of maternal blood to nourish the fetus. A poor extra-villous trophoblast invasion and uterine arterial remodeling can lead to fetal growth restriction and a serious pregnancy-associated maternal disease preeclampsia. Decorin, a leucine-rich proteoglycan produced by uterine decidual cells restrains multiple trophoblast functions: self-renewal and differentiation of trophoblast stem cells, migration, invasion, proliferation and endovascular differentiation. Additionally, decidual overproduction of decorin was associated with preeclampsia, and increased decorin levels in the maternal plasma during the second trimester could predict preeclampsia.
I discovered that decorin plays a critical role in maturation of human endometrial stromal cells into decidual cells. Using CRISPR-Cas9 approach for knocking out decorin, I showed that decorin-depleted human endometrial stromal cells failed to mature, as revealed by fibroblastic morphology and reduced production of decidual cell maturation markers, insulin like growth factor protein-1 and prolactin. I also found that interleukin 1 beta produced by trophoblast, macrophages and endometrial glands is the main stimulus for decorin production in the decidua by recruiting a transcription factor, nuclear factor kappa B. Additionally, I discovered a new microRNA-mediated mechanism of decorin action on trophoblast. Two microRNAs (let 7c-5p and 512-3p), induced by decorin restrained multiple trophoblast functions known to be compromised in preeclampsia. They were elevated in preeclampsia-associated placentas. Collectively, my research is fundamental to understanding the pathogenesis of preeclampsia. This knowledge can be exploited to improve maternal and fetal health. For example, decorin induced microRNAs may be used as a biomarker for early diagnosis and intervention of preeclampsia. Furthermore, non-toxic molecules that can reduce decorin production by decidual cells may have therapeutic potential.