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Kinetics and molecular hallmarks of the acquisition of developmental pluripotency during cellular reprogramming [ATAC-Seq]

ABSTRACT: The ability of induced pluripotent stem cells (iPSCs) to differentiate into all adult cell types makes them attractive for basic research and regenerative medicine applications, but it remains unknown when and how this hallmark of the pluripotent state is established. Here, we pinpoint the acquisition of developmental pluripotency in a suitable reprogramming system and show that nascent iPSCs abruptly and without extensive maturation period in culture become capable of generating all tissues upon injection into preimplantation embryos. Strikingly, the developmental potential of nascent iPSCs is comparable to or even surpasses that of high-quality established pluripotent cells. Further functional assays as well as genome-wide transcriptional and chromatin analyses suggest that cells acquiring developmental pluripotency exhibit a unique combination of molecular and functional properties that distinguish them from canonical pluripotency states. These include reduced clonal self-renewal potential and the elevated expression of transcriptional regulators of postimplantation development. Our observations close an important gap in our understanding of induced pluripotency and provide an improved roadmap of cellular reprogramming with ramifications for the biomedical use of iPSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE106331 | GEO | 2018/01/03

SECONDARY ACCESSION(S): PRJNA416318

REPOSITORIES: GEO

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Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.

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Kinetics and molecular hallmarks of the acquisition of developmental pluripotency during cellular reprogramming [ATAC-Seq]

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