Direct Induction of Trophoblast Stem Cells from Human Fibroblasts

Pregnancy complications with a basis of placental dysfunction such as preeclampsia and intra-uterine growth restriction (IUGR) are two common placental complications, constituting a major cause of mortality and morbidity for mother and child. Little is known regarding their etiology, in part because of a lack of appropriate in vitro modelling system. Also, many placental dysfunctions are detected only at late stages of pregnancy, when early placental progenitor cells are no longer available for isolation and propagation. It is therefore of paramount importance develop a platform that allows the production of early placental cells for the purpose of developing methods of early detection, prevention, and possible treatment of such disorders. Our research aims to generate stable and fully functional human induced trophoblast stem cells (hiTSCs), from skin cells (fibroblasts), by the transient expression of a small number of master regulatory genes. Based on evidence we have collected thus far, our hiTSCs undergo a stable conversion process and are generally indistinguishable from their human blastocyst-derived TSC counterparts. Gene expression and epigenome analyses as well as functional assays such as the formation of trophoblastic lesions in NOD-SCID mice and differentiation into trophoblastic cell types and the formation of functional organoids indicate fully reprogrammed functional TSCs. Finally, we show that the cells did not undergo a stage of pluripotency as indicated by the formation of hiTSCs from SOX2 KO fibroblasts. These results suggest that stable and fully functional human TSCs can be produced from differentiated cells and propose a new platform to model placental dysfunction diseases.