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Nuclear transfer is an effective reprogramming strategy that can redirect the utilization of nuclear instructions and ultimately phenotypes (1). When oocytes are used as the host, a somatic cell nucleus can be reprogrammed to activate the earliest stages of embryonic development (2, 3). Nuclear transfer embryos can develop until the stage when they are ready to implant into the uterus or shortly thereafter and then most degenerate. Very few nuclear transfer embryos successfully progress to term. Those that do mature are characterized by abnormalities in placentation, which in the mouse is placentomegaly (ref. 4 and Fig. 1). Recent reports, including one appearing in this issue of PNAS (5), investigate the etiology of this placentation defect in the mouse and arrive at somewhat different conclusions (5, 6). Placental development and TS cell derivation from fertilized and nuclear transfer embryos. Fertilized embryos developing in vivo generate placentas with two well-defined compartments: junctional zone and labyrinth zone. Nuclear transfer embryos developing past midgestation are rare events. However, those that do mature exhibit placentomegaly with a prominent expansion of the junctional zone. TS cells derived from either fertilized or nuclear transfer embryos are quite similar, including their abilities to successfully incorporate and function within a normally developing placenta (5). The implication from the research is that the trophoblast defects observed in nuclear transfer embryos are non-cell autonomous. Some issues potentially impacting this interpretation include in vitro cell selection. In the mouse, a population of stem cells can be isolated from embryonic day 3.5 blastocysts, or somewhat later from a structure referred to as extraembryonic ectoderm, and expanded in vitro (7). These cells are called trophoblast stem (TS) cells. They exhibit the capacity to self-renew and differentiate into each of the trophoblast cell lineages existing in the placenta (7). The latter point …

Trophoblast stem cells derived from nuclear transfer embryos: Phenotypically unique, bad neighbors, or poor communicators?