SUMMARY Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research.

Conventional embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) derived from primates resemble mouse epiblast stem cells, raising an intriguing question regarding whether the naive pluripotent state resembling mouse embryonic stem cells (mESCs) exists in primates and how to capture it in vitro. Here we identified several specific signaling modulators that are sufficient to generate rhesus monkey fibroblast-derived iPSCs with the features of naive pluripotency in terms of growth properties, gene expression profiles, self-renewal signaling, X-reactivation, and the potential to generate cross-species chimeric embryos. Interestingly, together with recent reports of naive human pluripotent stem cells, our findings suggest several conserved signaling pathways shared with rodents and specific to primates, providing significant insights for acquiring naive pluripotency from other species. In addition, the derivation of rhesus monkey naive iPSCs also provides a valuable cell source for use in preclinical research and disease modeling.

The applications of human pluripotent stem cell (hPSC)-derived cells in regenerative medicine has encountered a long-standing challenge: how can we efficiently obtain mature cell types from hPSCs? Attempts to address this problem are hindered by the complexity of controlling cell fate commitment and the lack of sufficient developmental knowledge for guiding hPSC differentiation. Here, we developed a systematic strategy to study hPSC differentiation by labeling sequential developmental genes to encompass the major developmental stages, using the directed differentiation of pancreatic β cells from hPSCs as a model. We therefore generated a large panel of pancreas-specific mono- and dual-reporter cell lines. With this unique platform, we visualized the kinetics of the entire differentiation process in real time for the first time by monitoring the expression dynamics of the reporter genes, identified desired cell populations at each differentiation stage and demonstrated the ability to isolate these cell populations for further characterization. We further revealed the expression profiles of isolated NGN3-eGFP(+) cells by RNA sequencing and identified sushi domain-containing 2 (SUSD2) as a novel surface protein that enriches for pancreatic endocrine progenitors and early endocrine cells both in human embryonic stem cells (hESC)-derived pancreatic cells and in the developing human pancreas. Moreover, we captured a series of cell fate transition events in real time, identified multiple cell subpopulations and unveiled their distinct gene expression profiles, among heterogeneous progenitors for the first time using our dual reporter hESC lines. The exploration of this platform and our new findings will pave the way to obtain mature β cells in vitro.

A reader has pointed out that there are duplications of some of the lanes presented in Figure 2B of our originally published manuscript. Upon examination of the affected lanes and the original data, we discovered that there is indeed duplication caused by inadvertent inclusion of erroneous image files during our organization of the published data.In Figure 2B of the original manuscript, the lanes of SALL4 presented are duplications of the lanes of CRIPTO, and the lanes of DNMT3B presented are duplications of the lanes of DPPA2. To correct this figure, we have replaced the indicated lanes with the correct data for SALL4, CRIPTO, DNMT3B, and DPPA2. All panels other than those indicated lanes remain the same. These unintentional mistakes in figure assembly do not affect our underlying data or conclusions. We apologize for any confusion caused by these unfortunate mistakes, and we wish to thank the anonymous reader for bringing them to our attention.The corrected figure is presented below.Cell Stem Cell 16, 211-212, February 5, 2015 ª2015 Elsevier Inc. 211

Background: The expression of suppressor of cytokine signaling 3 (SOCS3) was induced by interleukin-6 (IL-6) in preterm placental tissues. However, its role in IL-6 induced apoptosis of trophoblast cells derived from preterm placental tissues remains to be elucidated. Methods: Primary cytotrophoblasts from human preterm placental tissues were used to stably knock down and overexpress the level of SOCS3 by corresponding lentiviral vectors and the expression of SOCS3 was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The effect of SOCS3 overexpression or knockdown on the proliferation and apoptosis of IL-6 treated human cytotrophoblasts were determined by Cell Counting Kit-8 (CCK8) assay and Annexin-V/Propidium Iodide (PI) double-staining assay, respectively. Based on it, we detected the proteins associated with the Janus Tyrosine Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway and apoptosis, such as JAK2, p-JAK2, STAT3, p-STAT3, B-cell lymphoma-2 (Bcl-2) and BCL2-associated X (Bax) by Western blot.Results: IL-6-treatment resulted in significant apoptosis of human cytotrophoblasts. Overexpressing SOCS3 in the cytotrophoblasts reduced cell apoptosis, while the knockdown of SCOS3 had the opposite effects. Further analyses showed that SOCS3 overexpression inhibited JAK2 and STAT3 phosphorylation, which was induced by IL-6 stimulation.Conclusions: SOCS3 plays a protective role in human preterm placental tissue-derived cytotrophoblasts from IL-6 induced apoptosis by feedback inhibition of JAK2/STAT3 signaling.