E-Cadherin-Mediated Cell–Cell Contact Is Critical for Induced Pluripotent Stem Cell Generation  

Abstract

The low efficiency of reprogramming and genomic integration of virus vectors obscure the potential application of induced pluripotent stem (iPS) cells; therefore, identification of chemicals and cooperative factors that may improve the generation of iPS cells will be of great value. Moreover, the cellular mechanisms that limit the reprogramming efficiency need to be investigated. Through screening a chemical library, we found that two chemicals reported to upregulate E-cadherin considerably increase the reprogramming efficiency. Further study of the process indicated that E-cadherin is upregulated during reprogramming and the established iPS cells possess Ecadherin-mediated cell-cell contact, morphologically indistinguishable from embryonic stem (ES) cells. Our experiments also demonstrate that overexpression of E-cadherin significantly enhances reprogramming efficiency, whereas knockdown of endogenous E-cadherin reduces the efficiency. Consistently, abrogation of cell-cell contact by the inhibitory peptide or the neutralizing antibody against the extracellular domain of E-cadherin compromises iPS cell generation. Further mechanistic study reveals that adhesive binding activity of E-cadherin is required. Our results highlight the critical role of E-cadherin-mediated cell-cell contact in reprogramming and suggest new routes for more efficient iPS cell generation. STEM CELLS

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…Upregulation of epithelial genes, such as Cdh1 and Epcam, and downregulation of mesenchymal genes, such as Snai1/2 and Zeb1/2, take place early in reprogramming [7,115,116]. Consistent with this, factors promoting the epithelial state, such as TGF-β inhibitors, BMPs, microRNA miR200s and miR302/367, and Cdh1, enhance iPSC generation, and in some cases, are able to substitute for reprogramming factors [116,[157][158][159][160][161][162]. In contrast, factors that suppress the epithelial state (e.g., TGF-β) or depletion of key epithelial adhesion molecules (e.g., Figure 1 The path from a somatic cell to a refined iPSC and the putative epigenetic barriers during the process.…”

Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation

“…Although significant progress has been made in terms of improving the efficiency of iPS cell generation through the use of chemical compounds [46,47] and different cell types [48,49], interfering with the epigenetic status of donor cells [50][51][52], or modulating different signal pathways [34,53,54], the quality of iPS cells to date is not significantly improved or even getting worse when the p53 was absent to facilitate reprogramming [35]. On the other hand, regarding the safety concerns of iPS cells, strategies of generating integration-free iPS cells have been developed [55]; however, these reprogramming processes are extremely inefficient and the quality of resulting integration-free iPS cells still needs to be completely characterized [56].…”

microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

“…MET is required for reprogramming from fibroblasts to pluripotent cells [17,38]. The key epithelial gene E-cadherin is critically linked to pluripotency in ES cells and is essential for iPSC generation, and its expression is significantly increased after AZA treatment [17,[39][40][41]. The normal activation of the Dlk1-Dio3 imprinted region is positively correlated with the developmental potential of iPSCs [18,19].…”