Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs

By J. Hanna, A. Cheng, Krishanu Saha, Jongpil Kim, C. Lengner, F. Soldner, John P. Cassady, J. Muffat, Bryce W. Carey, R. Jaenisch. Proceedings of the National Academy of Sciences of the United States of America, 2010

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Human and mouse embryonic stem cells (ESCs) are derived from blastocyst-stage embryos but have very different biological properties, and molecular analyses suggest that the pluripotent state of human ESCs isolated so far corresponds to that of mouse-derived epiblast stem cells (EpiSCs). Here we rewire the identity of conventional human ESCs into a more immature state that extensively shares defining features with pluripotent mouse ESCs. This was achieved by ectopic induction of Oct4, Klf4, and Klf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3β (GSK3β) and mitogen-activated protein kinase (ERK1/2) pathway. Forskolin, a protein kinase A pathway agonist which can induce Klf4 and Klf2 expression, transiently substitutes for the requirement for ectopic transgene expression. In contrast to conventional human ESCs, these epigenetically converted cells have growth properties, an X-chromosome activation state (XaXa), a gene expression profile, and a signaling pathway dependence that are highly similar to those of mouse ESCs. Finally, the same growth conditions allow the derivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. The generation of validated “naïve” human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans and may open up new opportunities for patient-specific, disease-relevant research.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b752887d4166fcf6978e1764ad65f29a8d70b7b6

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Citations in the corpus

The Transcriptional and Epigenomic Foundations of Ground State Pluripotency (2012, background): “Currently there is great interest in isolating human pluripotent stem cells in a naive state (Hanna et al., 2010; Wang et al., 2011).”
Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency (2014, positive): “Initial studies reported that dual inhibition of MEK and GSK3 (2i), leukemia inhibitory factor (LIF), and overexpression of transcription factors associated with naive pluripotency can induce features of ground state pluripotency in human ESCs (Hanna et al., 2010; Wang et al., 2011).”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “Recent data from the Jaenisch laboratory (Hanna et al. 2010) indicate that overexpression of Oct4, Klf4, and Klf2, together with LIF and inhibitors of MAPK and GSK3 signaling, induces a metastable naı̈ve murine ESC-like state in human ESCs.”
Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human (2014, neutral): “Conversion of mouse EpiSCs to ESC may provide a paradigm for generation of human ground-state PSC. Early trials (Hanna et al., 2010; Wang et al., 2011) noted ESC-like morphology, but cells appeared unstable.”
Somatic cell reprogramming and transitions between pluripotent states: facts, hypotheses, unresolved issues (2010, positive): “, the addition of PD/CH inhibitors) and simultaneously overexpressing Oct4/Klf4 or addition of Forskolin to the medium (Figure 2B) (Hanna et al., 2010).”