A Small Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog

By J. Ichida, Joel W. Blanchard, Kelvin T Lam, Esther Y. Son, J. Chung, D. Egli, K. Loh, Ava C. Carter, F. D. Di Giorgio, Kathryn Koszka and 5 more. Cell Stem Cell, 2009

813 citations recorded by the source corpus.

Summary The combined activity of three transcription factors can reprogram adult cells into induced pluripotent stem (iPS) cells. However, the transgenic methods used to deliver reprogramming factors have raised concerns regarding the future utility of the resulting stem cells. These uncertainties could be overcome if each transgenic factor were replaced with a small molecule that either directly activated its expression from the somatic genome or in some way compensated for its activity. To this end, we have used high-content chemical screening to identify small molecules that can replace Sox2 in reprogramming. We show that one of these molecules functions in reprogramming by inhibiting Tgf-β signaling in a stable and trapped intermediate cell type that forms during the process. We find that this inhibition promotes the completion of reprogramming through induction of the transcription factor Nanog.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/982c52d55462395cc8feae01be81e35467fb71ba

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Citations in the corpus

Reprogramming of human primary somatic cells by OCT4 and chemical compounds. (2010, background): “…that can functionally replace exogenous reprogramming TFs and/or enhance the efficiency and kinetics of reprogramming (Shi et al., 2008; Huangfu et al., 2008; Lyssiotis et al., 2009; Ichida et al., 2009; Maherali and Hochedlinger, 2009; Lin et al., 2009; Li et al., 2009; Esteban et al., 2010).”
Conversion of Mouse and Human Fibroblasts into Functional Spinal Motor Neurons (2011, methodology): “Immunocytochemistry Antibody staining was performed as previously described (Ichida et al., 2009).”
A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. (2010, background): “, 2009) and improves mouse (Ichida et al., 2009; Maherali and Hochedlinger, 2009) and human (Lin et al.”
Somatic cell reprogramming and transitions between pluripotent states: facts, hypotheses, unresolved issues (2010, neutral): “Reprogramming can be induced not only by Oct4, Sox2, Klf4, and c-Myc but also by alternative combinations that employ Nanog, Lin28, ESRRB, NR5A2, and other genes that promote the establishment of the core transcriptional circuitry of stem cells (Ichida et al., 2009; Yu et al., 2007).”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “Although inhibition of TGF-β signalling improves reprogramming by inducing Nanog in mouse cells, it may also promote the mesenchymal-to-epithelial transition, which is required in the early stages of reprogramming of mouse and human fibroblasts to iPS cells (Li et al., 2010; Samavarchi-Tehrani et al”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “This was seen in both mouse (Ichida et al. 2009; Maherali and Hochedlinger 2009) and human fibroblasts (T Lin et al.”