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Kinetic Measurement and Real Time Visualization of Somatic Reprogramming
Published on: July 30, 2016
Jak/Stat3 signaling promotes somatic cell reprogramming by epigenetic regulation
Yong Tang1, Yan Luo, Zongliang Jiang
1Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, Connecticut 06269, USA.
Stem Cells (Dayton, Ohio)
|September 13, 2012
Summary
Leukemia inhibitory factor (LIF) and Janus kinase/signal transducer and activator of transcription 3 (Jak/Stat3) pathway activation are essential for establishing pluripotency in mouse embryonic fibroblasts. This pathway regulates epigenetic modifications, including DNA demethylation and chromatin remodeling, crucial for reprogramming.
Area of Science:
- Stem cell biology
- Epigenetics
- Cellular reprogramming
Background:
- Leukemia inhibitory factor (LIF) maintains pluripotency in mouse embryonic stem cells and induced pluripotent stem cells (iPSCs) via the Janus kinase/signal transducer and activator of transcription 3 (Jak/Stat3) pathway.
- Stat3's role in reprogramming has been observed in epiblast and neural stem cells, but its precise mechanism in terminally differentiated cells was unclear.
Purpose of the Study:
- To investigate the role and mechanism of Jak/Stat3 activation in the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs).
- To determine if Jak/Stat3 signaling is essential for epigenetic changes during reprogramming.
Main Methods:
- Utilized mouse embryonic fibroblasts (MEFs) for reprogramming experiments.
- Inhibited Jak/Stat3 activity using specific inhibitors.
- Assessed DNA methylation of Oct4 and Nanog regulatory elements.
- Measured expression levels of DNA methyltransferases (Dnmt), histone deacetylases (HDACs), and other epigenetic modifiers.
- Investigated the effect of Dnmt or HDAC inhibitors on reprogramming efficiency.
Main Results:
- Activated Stat3 is essential for pluripotency establishment in MEFs during reprogramming.
- Jak/Stat3 inhibition blocked demethylation of Oct4 and Nanog regulatory elements, suppressed pluripotent gene expression, and increased Dnmt and HDAC expression.
- Jak/Stat3 inhibition also prevented retroviral transgene silencing by blocking Dnmt3L expression.
- Dnmt or HDAC inhibitors rescued reprogramming arrested by Jak/Stat3 inhibition or LIF deprivation.
- LIF/Stat3 signaling is a prerequisite for complete reprogramming of partially reprogrammed cells (pre-iPSCs).
Conclusions:
- Jak/Stat3 activity is fundamental for promoting pluripotency establishment at the epigenetic level during late-stage reprogramming.
- This involves facilitating DNA demethylation/de novo methylation and open-chromatin formation.
- The LIF/Stat3 pathway is critical for successful reprogramming of MEFs and pre-iPSCs.
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