Hans Robert Schöler

During the peri-implantation phase of murine embryogenesis, the epiblast proliferates rapidly and undergoes epithelialization. At the same time, the preimplantation pluripotent state transforms into a more developmentally advanced, pregastrulation state. While extensive research has elucidated cell-extrinsic signals that direct the developmental progression, such as the Fgf/Mek/Erk pathway, the potential interplay of intrinsic cellular cues remains largely unexplored. To address this, we conducted a comprehensive phenotypic screen using an in vitro model of epiblast development. We identified aurora kinase A as a cell-intrinsic factor contributing to Erk activation and transcriptional response. Consequently, suppressing aurora kinase A activity delayed exit from naïve pluripotency. Moreover, our results show that upon entry into mitosis, Erk relocates to the cell division machinery. We found that in dividing cells, a fraction of Erk, with yet elusive functions, localizes on the centrosomes, where its phosphorylation depends on polo-like kinase 1.

Embryo implantation is accompanied by the naïve-to-primed pluripotency transition in epiblast cells, making them receptive to external differentiation signals. In addition to this developmental program switch, implantation suggests that an anabolic boost is required for this process, as the embryo-uterine connection begins supplying the requisite nutrients. In this study, we show that the DNA-binding protein Pcbp1 plays a key role in intensifying amino acid metabolism during the priming of pluripotent stem cells. Knockout of the Pcbp1 gene leads to embryo growth arrest a few days after implantation. By modeling the naïve-to-primed pluripotency transition in vitro , we observe reduced proliferation and induction of apoptosis in cells deficient for Pcbp1. Using multi-omics approaches, we uncover a crucial role for Pcbp1 in driving a transcriptional burst of numerous genes involved in the import and the de novo synthesis of essential and conditionally essential amino acids. Pcbp1 deficiency is consequently associated with a slowdown in protein biosynthesis, explaining the early lethal phenotype of knockout embryos. Our findings thus uncover the molecular mechanisms underlying anabolic changes during the naïve-to-primed pluripotency transition and highlight the essential role of Pcbp1 in this process, also pointing to its functions in highly proliferative cells. Graphical

Conventional understanding dictates that mammalian neural stem cells (NSCs) exist only in the central nervous system. Here, we report that peripheral NSCs (pNSCs) exist outside the central nervous system and can be isolated from mouse embryonic limb, postnatal lung, tail, dorsal root ganglia and adult lung tissues. Derived pNSCs are distinct from neural crest stem cells, express multiple NSC-specific markers and exhibit cell morphology, self-renewing and differentiation capacity, genome-wide transcriptional profile and epigenetic features similar to control brain NSCs. pNSCs are composed of Sox1⁺ cells originating from neuroepithelial cells. pNSCs in situ have similar molecular features to NSCs in the brain. Furthermore, many pNSCs that migrate out of the neural tube can differentiate into mature neurons and limited glial cells during embryonic and postnatal development. Our discovery of pNSCs provides previously unidentified insight into the mammalian nervous system development and presents an alternative potential strategy for neural regenerative therapy.

During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 gradually come into play in the early ICM, coinciding with the initiation of Sox2 expression. Oct4 and Sox2 activate the pluripotency-related genes through the putative OCT-SOX enhancers in the early ICM. Furthermore, we observed a substantial reorganization of chromatin landscape and transcriptome from the morula to the early ICM stages, which was partially driven by Oct4 and Sox2, highlighting their pivotal role in promoting the developmental trajectory toward the ICM. Our study provides new insights into the establishment of the pluripotency network in mouse preimplantation embryos.

During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 gradually come into play in the early ICM, coinciding with the initiation of Sox2 expression. Oct4 and Sox2 activate the pluripotency-related genes through the putative OCT-SOX enhancers in the early ICM. Furthermore, we observed a substantial reorganization of chromatin landscape and transcriptome from the morula to the early ICM stages, which was partially driven by Oct4 and Sox2, highlighting their pivotal role in promoting the developmental trajectory towards the ICM. Our study provides new insights into the establishment of the pluripotency network in mouse preimplantation embryos.

Junmyeong Park, Jueun Kim, Borami Shin, Hans R Schöler, Johnny Kim, Kee-Pyo Kim. IJSC -0001;0:. https://doi.org/10.15283/ijsc23148

Over the past decade, there has been a dramatic increase in efforts to ameliorate aging and the diseases it causes, with transient expression of nuclear reprogramming factors recently emerging as an intriguing approach. Expression of these factors, either systemically or in a tissue-specific manner, has been shown to combat age-related deterioration in mouse and human model systems at the cellular, tissue and organismal level. Here we discuss the current state of epigenetic rejuvenation strategies via partial reprogramming in both mouse and human models. For each classical reprogramming factor, we provide a brief description of its contribution to reprogramming and discuss additional factors or chemical strategies. We discuss what is known regarding chromatin remodeling and the molecular dynamics underlying rejuvenation, and, finally, we consider strategies to improve the practical uses of epigenetic reprogramming to treat aging and age-related diseases, focusing on the open questions and remaining challenges in this emerging field.