Chemical conversion of human conventional Pluripotent Stem Cells to Trophoblast Stem Cells

Abstract: In human embryos, naive pluripotent cells of the inner cell mass generate epiblast, primitive endoderm and Trophectoderm (TE) lineage, whence trophoblast cells derive. In vitro, naive pluripotent stem cells (PSCs) retain this potential and can generate trophoblast stem cells (TSCs), while conventional PSCs form amnion-like cells and lack the competence to generate TSCs. Transient histone deacetylase and MEK inhibitions with LIF stimulation can be used to chemically reset conventional to naive PSCs. Here we report that chemical resetting induced expression of both naive and TSC markers and of placental imprinted genes. A modified chemical resetting protocol allowed for the fast and efficient conversion of conventional PSCs into TSCs, entailing shutdown of pluripotency genes and full activation of the trophoblast master regulators, without induction of amnion markers. Chemical resetting generates a responsive intermediate state, in which conventional PSCs rapidly acquire competence to form TSCs without the need of stabilisation and expansion in a naive state. The efficiency and rapidity of our system will be useful for the study of cell fate transitions, and to generate models of placental disorders.