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Multiple pluripotent states have been described in mouse and human stem cells. Here the authors describe trajectories during BMP4 induced primed to naïve transition, which bifurcates into naïve and trophoblast-like branches with a PGC-like intermediate at the naïve branch.

Abstract Forkhead box (Fox) transcription factors play important roles in mammalian development and disease. However, their function in mouse somatic cell reprogramming remains unclear. Here, we report that FoxD subfamily and FoxG1 accelerate induced pluripotent stem cells (iPSCs) generation from mouse fibroblasts as early as day4 while FoxA and FoxO subfamily impede this process obviously. More importantly, FoxD3, FoxD4 and FoxG1 can replace Oct4 respectively and generate iPSCs with germline transmission together with Sox2 and Klf4. On the contrary, FoxO6 almost totally blocks reprogramming through inhibiting cell proliferation, suppressing the expression of pluripotent genes and hindering the process of mesenchymal to epithelial transition (MET). Thus, our study uncovers unexpected roles of Fox transcription factors in reprogramming and offers new insights into cell fate transition.

Emerging evidence suggests that exit from pluripotency is a regulated, rather than passive process. Here the authors identify a requirement for SS18-mediated Brg/Brahma-associated factors (BAF) chromatin remodeling complex assembly during exit from pluripotency, and that SS18 promotes BAF assembly through liquidliquid phase separation.

The static magnetic fields (SMFs) impact on biological systems, induce a variety of biological responses, and have been applied to the clinical treatment of diseases. However, the underlying mechanisms remain largely unclear. In this report, by using human mesenchymal stem cells (MSCs) as a model, we investigated the biological effect of SMFs at a molecular and cellular level. We showed that SMF exposure promotes MSC proliferation and activates the expression of transcriptional factors such as FOS (Fos Proto-Oncogene, AP-1 Transcription Factor Subunit) and EGR1 (Early Growth Response 1). In addition, the expression of signal-transduction proteins p-ERK1/2 and p-JNK oscillate periodically with SMF exposure time. Furthermore, we found that the inhibition of the T-type calcium ion channels negates the biological effects of SMFs on MSCs. Together, we revealed that the SMFs regulate T-type calcium ion channels and mediate MSC proliferation via the MAPK signaling pathways.

Polycomb repressive complex 1 (PRC1) plays essential roles in cell-fate determination. Recent studies have found that the composition of mammalian PRC1 is particularly varied and complex; however, little is known about the functional consequences of these variant PRC1 complexes on cell-fate determination. Here, we show that Kdm2b promotes Oct4-induced somatic reprogramming through recruitment of a variant PRC1 complex (PRC1.1) to CpG islands (CGIs). Furthermore, we find that bone morphogenetic protein (BMP) represses Oct4/Kdm2b-induced somatic reprogramming selectively. Mechanistically, BMP-SMAD pathway attenuates PRC1.1 occupation and H2AK119 ubiquitination at genes linked to development, resulting in the expression of mesendodermal factors such as Sox17 and a consequent suppression of somatic reprogramming. These observations reveal that PRC1.1 participates in the establishment of pluripotency and identify BMP4 signaling as a modulator of PRC1.1 function.

Summary: Reprogramming somatic cells to pluripotency by Oct4, Sox2, Klf4, and Myc represent a paradigm for cell fate determination. Here, we report a combination of Jdp2, Jhdm1b, Mkk6, Glis1, Nanog, Essrb, and Sall4 (7F) that reprogram mouse embryonic fibroblasts or MEFs to chimera competent induced pluripotent stem cells (iPSCs) efficiently. RNA sequencing (RNA-seq) and ATAC-seq reveal distinct mechanisms for 7F induction of pluripotency. Dropout experiments further reveal a highly cooperative process among 7F to dynamically close and open chromatin loci that encode a network of transcription factors to mediate reprogramming. These results establish an alternative paradigm for reprogramming that may be useful for analyzing cell fate control. : Wang et al. report a 7F reprogramming system for iPSC generation and the underlying mechanism for inducing pluripotency through a TF network, opening an alternative path for reprogramming cell fate.

Safety issues associated with transcription factors or viruses may be avoided with the use of chemically induced pluripotent stem cells (CiPSCs), thus promoting their clinical application. Previously, we had successfully developed and standardized an induction method using small-molecule compound, with simple operation, uniform induction conditions, and clear constituents. In order to verify that the CiPSCs were indeed reprogrammed from mouse embryonic fibroblasts (MEFs), and further explore the underlying mechanisms, FSP-tdTomato mice were used to construct a fluorescent protein-tracking system of MEFs, for revealing the process of CiPSC reprogramming. CiPSCs were identified by morphological analysis, mRNA, and protein expression of pluripotency genes, as well as teratoma formation experiments. Results showed that after 40-day treatment of tdTomato-MEFs with small-molecule compounds, the cells were presented with prominent nucleoli, high core-to-cytoplasmic ratio, round shape, group and mass arrangement, and high expression of pluripotency gene. These cells could differentiate into three germ layer tissues in vivo. As indicated by the above results, tdTomato-MEFs could be reprogrammed into CiPSCs, a lineage that possesses pluripotency similar to mouse embryonic stem cells (mESCs), with the use of small-molecule compounds. The establishment of CiPSC lineage, tracked by fluorescent protein, would benefit further studies exploring its underlying mechanisms. With continuous expression of fluorescent proteins during cellular differentiation, this cell lineage could be used for tracking CiPSC transplantation and differentiation into functional cells.

We report here an approach to redirecting somatic cell fate under chemically defined conditions without transcription factors. We start by converting mouse embryonic fibroblasts to epithelial-like cells with chemicals and growth factors. Subsequent cell fate mapping reveals a robust induction of SOX17 in the resulting epithelial-like cells that can be further reprogrammed to endodermal progenitor cells. Interestingly, these cells can self-renew in vitro and further differentiate into albumin- producing hepatocytes that can rescue mice from acute liver injury. Our results demonstrate a rational approach to convert mouse embryonic fibroblasts to hepatocytes and suggest that this mechanism-driven approach may be generalized for other cells. [ABSTRACT FROM AUTHOR]