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In vivo Reprogramming of Adult Somatic Cells to Pluripotency by Overexpression of Yamanaka Factors
Published on: December 17, 2013
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Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem
Sergio Ruiz1, Andres J Lopez-Contreras1, Mathieu Gabut2,3
1Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
Nature Communications
|August 22, 2015
Summary
Reprogramming adult cells into induced pluripotent stem cells (iPSC) can cause genomic instability due to replication stress. Lowering this stress by increasing checkpoint kinase 1 (CHK1) or supplementing nucleosides improves iPSC generation and genomic stability.
Area of Science:
- Stem cell biology
- Genomics
- Molecular biology
Background:
- Induced pluripotent stem cells (iPSC) offer therapeutic potential but exhibit genomic instability.
- The underlying causes of genomic instability in iPSC are not fully understood.
- Replication stress is implicated in genomic instability.
Purpose of the Study:
- To investigate the role of replication stress in iPSC generation.
- To identify strategies for reducing genomic instability during reprogramming.
Main Methods:
- Studied the effect of reprogramming factors on replication stress.
- Manipulated checkpoint kinase 1 (CHK1) levels.
- Administered nucleoside supplementation during reprogramming.
- Assessed genomic stability in mouse and human iPSC.
Main Results:
- Reprogramming factors induce replication stress, similar to oncogene-induced stress.
- Increased CHK1 levels reduced replication stress and enhanced iPSC generation efficiency.
- Nucleoside supplementation decreased DNA damage and genomic rearrangements in iPSC.
- Both genetic and chemical methods to lower replication stress improved iPSC genomic stability.
Conclusions:
- Replication stress is a key driver of genomic instability during iPSC generation.
- Modulating replication stress pathways offers a viable strategy to improve iPSC quality.
- Reducing genomic instability enhances the safety and efficacy of iPSC for biomedical applications.
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