Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural–functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought.

Proper trophoblast development is essential for placental function and is a key determinant of pregnancy outcomes. Three-dimensional spheroid and organoid cultures using cells from placental tissues or trophoblast stem cells have emerged as models that recapitulate cell–cell interactions and aspects of the physiological environment. Trophoblast organoids typically contain self-renewing cytotrophoblasts located toward the periphery in contact with basement membrane, whereas cells within the core fuse into hormone-producing syncytiotrophoblasts. Removing cells from matrix and/or culturing them in suspension can reverse this organization. In both cases, spontaneous syncytialization occurs, but the underlying mechanisms remain poorly understood. To identify signaling pathways associated with spontaneous trophoblast differentiation in three-dimensional conditions, human trophoblast stem cells were either maintained in the stem state as two-dimensional (2D) monolayers or aggregated in suspension without an exogenous matrix to form three-dimensional cultures. Expression and localization of trophoblast subpopulation markers were compared between two- and three-dimensional cultures. Three-dimensional cultures displayed increased spontaneous differentiation into the syncytiotrophoblast lineage along the periphery, accompanied by reduced proliferation of cytotrophoblasts. Consistent with this observation, BeWo choriocarcinoma cells exhibited increased chorionic gonadotropin levels in three-dimensional culture, whereas this response was not observed in HTR8/SVneo immortalized trophoblasts. Gene expression and pathway enrichment analyses identified Hippo signaling as altered in three-dimensional trophoblast stem cell cultures, with reduced expression of several genes associated with YAP1/TAZ-TEAD transcriptional activity. Inhibition of LATS1/2, which activates YAP1/TAZ-TEAD signaling, reduced spontaneous syncytiotrophoblast formation. These findings suggest that reduced YAP1/TAZ-TEAD activity may facilitate self-organized syncytialization in three-dimensional trophoblast cultures.