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Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4
Published on: April 7, 2008
Gene expression of OCT4, SOX2, KLF4 and MYC (OSKM) induced pluripotent stem cells: identification for potential
Yanning Cai1,2, Xianhua Dai3,4, Qianhua Zhang5,6
1School of Information Science and Technology, Sun Yat-sen University, Higher Education Mega Center, No.132 East Outer Ring Road, Guangzhou, China. caiyanningmitl@sina.com.
Background:
Somatic cells could be reprogrammed to induced pluripotent stem cells (iPS) by ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM). We aimed to gain insights into the early mechanisms underlying the induction of pluripotency.
Methods:
GSE28688 containing 14 gene expression profiles were downloaded from GEO, including untreated human neonatal foreskin fibroblasts (HFF1) as control, OSKM-induced HFF1 (at 24, 48, 72 h post-transduction of OSKM encoding viruses), two iPS cell lines, and two embryonic stem (ES) cell lines. Differentially expressed genes (DEGs) were screened between different cell lines and the control by Limma package in Bioconductor. KEGG pathway enrichment analysis was performed by DAVID. The STRING database was used to construct protein-protein interaction (PPI) network. Activities and regulatory networks of transcription factors (TFs) were calculated and constructed by Fast Network Component Analysis (FastNCA).
Results:
Compared with untreated HFF1, 117, 347, 557, 2263 and 2307 DEGs were obtained from three point post-transduction HFF1, iPS and ES cells. Meanwhile, up-regulated DEGs in first two days of HFF1 were mainly enriched in RIG-I-like receptor (RLR) and Toll-like receptor (TLR) signaling pathways. Down-regulated DEGs at 72 h were significantly enriched in focal adhesion pathway which was similar to iPS cells. Moreover, ISG15, IRF7, STAT1 and DDX58 were with higher degree in PPI networks during time series. Furthermore, the targets of six selected TFs were mainly enriched in screened DEGs.
Conclusion:
In this study, screened DEGs including ISG15, IRF7 and CCL5 participated in OSKM-induced pluripotency might attenuate immune response post-transduction through RLR and TLR signaling pathways.
Virtual Slides:
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2503890341543007 .
Insights
Reprogramming somatic cells to induced pluripotent stem cells (iPS) using OSKM factors may involve early immune response attenuation. Key genes like ISG15, IRF7, and CCL5 appear to modulate RIG-I-like receptor and Toll-like receptor signaling pathways.
Area of Science:
- Stem cell biology
- Molecular biology
- Immunology
Background:
- Somatic cells can be reprogrammed to induced pluripotent stem cells (iPS) through the ectopic expression of OCT4, SOX2, KLF4, and MYC (OSKM).
- Understanding the early molecular mechanisms driving pluripotency induction is crucial for advancing regenerative medicine and developmental biology.
Purpose of the Study:
- To investigate the early molecular events and gene expression changes during OSKM-induced reprogramming.
- To identify key pathways and regulatory networks involved in the initial stages of pluripotency induction.
Main Methods:
- Analysis of gene expression profiles from human neonatal foreskin fibroblasts (HFF1) at various time points post-OSKM transduction, alongside iPS and embryonic stem (ES) cell lines.
- Screening for differentially expressed genes (DEGs) using the Limma package, followed by KEGG pathway enrichment analysis via DAVID.
- Construction of protein-protein interaction (PPI) networks using STRING and analysis of transcription factor (TF) regulatory networks with FastNCA.
Main Results:
- A significant number of DEGs were identified across different time points and cell types, with early up-regulated DEGs enriched in RIG-I-like receptor (RLR) and Toll-like receptor (TLR) signaling pathways.
- Down-regulated DEGs at 72 hours post-transduction were enriched in the focal adhesion pathway, similar to iPS cells.
- Key genes such as ISG15, IRF7, STAT1, and DDX58 showed high network degrees, and selected TFs targeted genes enriched within the identified DEGs.
Conclusions:
- The study suggests that DEGs, including ISG15, IRF7, and CCL5, play a role in OSKM-induced pluripotency.
- These genes may contribute to attenuating the immune response during the reprogramming process via RLR and TLR signaling pathways.
- This finding provides insights into the interplay between pluripotency induction and innate immune signaling.
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