Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT–MET mechanism for optimal reprogramming

Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

Zhao, C., Deng, W. & Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).

Kim, D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem. Cell 4, 472–476 (2009).

Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. & Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949–953 (2008).

Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem. Cell 7, 618–630 (2010).

Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem. Cell 4, 381–384 (2009).

Liao, J. et al. Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem. Cell 4, 11–15 (2009).

Liu, H. et al. Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem. Cell 3, 587–590 (2008).

Nelson, T. J., Martinez-Fernandez, A. & Terzic, A. Induced pluripotent stem cells: developmental biology to regenerative medicine. Nat. Rev. Cardiol. 7, 700–710 (2010).

Cheng, L. et al. Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem. Cell 10, 337–344 (2012).

Hussein, S. M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011).

Fairchild, P. J. The challenge of immunogenicity in the quest for induced pluripotency. Nat. Rev. Immunol. 10, 868–875 (2010).

Zhao, T., Zhang, Z. N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).

Young, M. A. et al. Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem. Cell 10, 570–582 (2012).

Esteban, M. A. et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem. Cell 6, 71–79 (2010).

Wang, T. et al. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem. Cell 9, 575–587 (2011).

Chen, J. et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat. Genet. 45, 34–42 (2012).

Esteban, M. A. & Pei, D. Vitamin C improves the quality of somatic cell reprogramming. Nat. Genet. 44, 366–367 (2012).

Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63 (2010).

Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009).

Buganim, Y. et al. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 150, 1209–1222 (2012).

Carey, B. W. et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc. Natl Acad. Sci. USA 106, 157–162 (2009).

Pan, G., Li, J., Zhou, Y., Zheng, H. & Pei, D. A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. FASEB J. 20, 1730–1732 (2006).

Ruiz, S. et al. A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr. Biol. 21, 45–52 (2010).

Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem. Cell 7, 64–77 (2010).

Conacci-Sorrell, M. et al. Autoregulation of E-cadherin expression by cadherin–cadherin interactions: the roles of β-catenin signaling, Slug, and MAPK. J. Cell Biol. 163, 847–857 (2003).

Maeda, M., Johnson, K. R. & Wheelock, M. J. Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J. Cell Sci. 118, 873–887 (2005).

Shih, J. Y. & Yang, P. C. The EMT regulator slug and lung carcinogenesis. Carcinogenesis 32, 1299–1304 (2011).

Alves, C. C., Carneiro, F., Hoefler, H. & Becker, K.F. Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci. 14, 3035–3050 (2009).

Schulte, J. et al. Expression of the E-cadherin repressors Snail, Slug and Zeb1 in urothelial carcinoma of the urinary bladder: relation to stromal fibroblast activation and invasive behaviour of carcinoma cells. Histochem. Cell Biol. 138, 847–860 (2012).

Wels, C., Joshi, S., Koefinger, P., Bergler, H. & Schaider, H. Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial-mesenchymal transition-like phenotype in melanoma. J. Invest. Dermatol. 131, 1877–1885 (2011).

Chiou, S. H. et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 70, 10433–10444 (2010).

Liu, Y. N. et al. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition. Mol. Cell. Biol. 32, 941–953 (2012).

Ichida, J. K. et al. A small-molecule inhibitor of tgf- β signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem. Cell 5, 491–503 (2009).

Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151, 994–1004 (2012).

Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).

Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).

Palma-Nicolas, J. P. & Lopez-Colome, A. M. Thrombin induces slug-mediated E-cadherin transcriptional repression and the parallel Up-regulation of N-cadherin by a transcription-independent mechanism in RPE cells. J. Cell. Physiol. 228, 581–589 (2013).

Gravdal, K., Halvorsen, O. J., Haukaas, S. A. & Akslen, L. A. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin. Cancer Res. 13, 7003–7011 (2007).

Baum, B., Settleman, J. & Quinlan, M. P. Transitions between epithelial and mesenchymal states in development and disease. Sem. Cell Dev. Biol. 19, 294–308 (2008).

Lim, J. & Thiery, J. P. Epithelial-mesenchymal transitions: insights from development. Development 139, 3471–3486 (2012).

Davies, J. A. Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anatom. 156, 187–201 (1996).

Nakaya, Y., Kuroda, S., Katagiri, Y. T., Kaibuchi, K. & Takahashi, Y. Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1. Dev. Cell 7, 425–438 (2004).

Nakajima, Y., Yamagishi, T., Hokari, S. & Nakamura, H. Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)- β and bone morphogenetic protein (BMP). Anatom. Rec. 258, 119–127 (2000).

Li, B., Zheng, Y. W., Sano, Y. & Taniguchi, H. Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation. PloS One 6, e17092 (2011).

Trusolino, L., Bertotti, A. & Comoglio, P. M. MET signalling: principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 11, 834–848 (2010).

Silva, J. et al. Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol. 6, e253 (2008).

Qin, D. et al. Mouse meningiocytes express Sox2 and yield high efficiency of chimeras after nuclear reprogramming with exogenous factors. J. Biol. Chem. 283, 33730–33735 (2008).

Chen, J. et al. Rational optimization of reprogramming culture conditions for the generation of induced pluripotent stem cells with ultra-high efficiency and fast kinetics. Cell Res. 21, 884–894 (2011).