UC San Diego

Previous studies have shown the fatal effects of BMP treatment on early mouse blastocysts, but never in isolated trophoblast stem cells. The question being addressed in this research investigates the role of BMP signaling in mouse trophoblast stem cell maintenance and differentiation. TSC are evaluated through the addition and removal of BMP signaling via exogenous Bmp4, overexpression of Bmp4, knockdown of Bmpr2, and small molecule inhibitors. The addition of exogenous Bmp4 inhibited some differentiation markers, while the overexpression of Bmp4 inhibited all the differentiation markers tested. However, there was insufficient knockdown of Bmpr2 using inducible shRNA, leading to the use of small molecule inhibitors to remove BMP signaling. The use of LDN193189, DMH1, 5Z-7-Oxozeaenol, and Takinib in TSC cultures resulted in the largest effect morphologically and in differentiation markers with 5Z-7-Oxozeaenol, targeting the non-canonical BMP signaling pathway. Although TAK1 was determined not to be the target of 5Z-7-Oxozeaenol, suggesting other targets such as NF-κB or JNK/p38. Overall, the findings suggest that BMP signaling maintains TSC in their undifferentiated state and inhibits differentiation into their respective lineages. Importantly, this study may provide more insight on how BMP signaling affects early mouse placental development and is thus relevant to placental complications such as pre-term birth, preeclampsia, and placenta accreta.