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Generation of Integration-free Induced Pluripotent Stem Cells from Human Peripheral Blood Mononuclear Cells Using Episomal Vectors
Published on: January 1, 2017
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C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells
Bruno Di Stefano1, Jose Luis Sardina2, Chris van Oevelen2
11] Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain.
Nature
|December 17, 2013
Summary
CCAAT/enhancer binding protein-α (C/EBPα) enhances induced pluripotent stem (iPS) cell reprogramming by increasing chromatin accessibility. It also upregulates Tet2, a dioxygenase crucial for demethylating pluripotency genes and linking iPS cell generation with B-cell transdifferentiation.
Area of Science:
- Cell Biology
- Stem Cell Research
- Epigenetics
Background:
- CCAAT/enhancer binding protein-α (C/EBPα) is known to induce B-cell transdifferentiation into macrophages and enhance induced pluripotent stem (iPS) cell reprogramming when combined with Oct4, Sox2, Klf4, and Myc (OSKM).
- The precise mechanisms by which C/EBPα exerts these effects remain largely unelucidated.
Purpose of the Study:
- To investigate the underlying mechanisms of C/EBPα-mediated enhancement of iPS cell reprogramming and B-cell transdifferentiation.
- To identify key molecular players involved in C/EBPα's function during these cellular conversion processes.
Main Methods:
- Utilized mouse primary B cells for reprogramming experiments.
- Assessed iPS cell reprogramming efficiency and pluripotency gene expression following transient C/EBPα expression and subsequent OSKM activation.
- Investigated chromatin accessibility using DNase I sensitivity assays.
- Examined the role and localization of Tet2 during the reprogramming process.
- Overexpressed Tet2 to evaluate its impact on reprogramming efficiency.
Main Results:
- Transient C/EBPα expression followed by OSKM activation dramatically increased iPS cell reprogramming efficiency by 100-fold in 95% of mouse primary B cells.
- Pluripotency and epithelial-mesenchymal transition genes were significantly upregulated, with 60% of cells expressing Oct4 within two days.
- C/EBPα acted as a 'path-breaker' by transiently increasing chromatin accessibility to pluripotency genes.
- C/EBPα induced Tet2 expression and nuclear translocation, where Tet2 bound to regulatory regions of pluripotency genes, facilitating their demethylation.
- Tet2 overexpression enhanced OSKM-induced reprogramming, and Tet2 was essential for C/EBPα-induced B-cell conversion.
Conclusions:
- Tet2 acts as a crucial mechanistic link between C/EBPα-induced B-cell transdifferentiation and enhanced iPS cell reprogramming.
- The findings reveal a novel role for C/EBPα in modulating chromatin accessibility and Tet2 activity for efficient cellular reprogramming.
- This rapid reprogramming approach offers potential for further mechanistic studies and clinical applications in regenerative medicine.
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