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Summary: Ectopic expression of Oct4, Sox2, Klf4, and c-Myc can reprogram differentiated somatic cells into induced pluripotent stem cells (iPSCs). For years, Oct4 has been considered the key reprogramming factor core of the four factors. Here, we challenge this view by reporting a core function of Sox2 and Klf4 in reprogramming. We found that polycistronic expression of Sox2 and Klf4 was sufficient to induce pluripotency in the absence of exogenous Oct4, and the stoichiometry of Sox2 and Klf4 was essential. Sox2 and Klf4 cooperatively bound across the genome, leading to epigenetic remodeling of their targets, including pluripotency genes and gradual activation of the pluripotency network. Interestingly, cells of different germ layer origins, fibroblasts (mesoderm) and neural progenitor cells (ectoderm), showed convergent reprogramming trajectories and similar efficiency. This work demonstrates a core function of Sox2 and Klf4 in pluripotency induction and shows that this mechanism is independent of germ layer origin. : An et al. report that polycistronic Sox2 and Klf4 induced pluripotency in multiple cell types, and the factor stoichiometry and cooperativity are essential for pluripotency network activation. This work demonstrates a core function of Sox2 and Klf4 in pluripotency induction and a mechanism independent of germ layer origin. Keywords: stoichiometry, cooperativity, reprogramming, Sox2, Klf4, pluripotency

Summary: Trophoblast stem (TS) cells are increasingly used as a model system for studying placentation and placental disorders. However, practical limitations of genetic manipulation have posed challenges for genetic analysis using TS cells. Here, we report the generation of mouse parthenogenetic haploid TS cells (haTSCs) and show that supplementation with FGF4 and inhibition of Rho-associated protein kinase (ROCK) enable the maintenance of their haploidy and developmental potential. The resulting haTSCs have 20 chromosomes, exhibit typical expression features of TS cells, possess the multipotency to differentiate into specialized trophoblast cell types, and can chimerize E13.5 and term placentas. We also demonstrate the capability of the haTSCs to undergo genetic manipulation and facilitate genome-wide screening in the trophoblast lineage. We expect that haTSCs will offer a powerful tool for studying functional genomics and placental biology. : Trophoblast stem (TS) cells are increasingly used as a model system for studying placentation and placental disorders. Here, Cui et al. report the generation of mouse haploid TS cells, which possess a wide extraembryonic developmental potential and can serve as a powerful tool for studying functional genomics and placental biology. Keywords: haploidy, trophoblast, stem cells, TSC