Induced pluripotent stem(iPS) cells


 Induced pluripotent stem (iPS) cells are pluripotent cells derived from any differentiated cell type through ectopic expression of transcription factors. By definition, pluripotency is the ability of a cell to give rise to all cell types of an adult organism, without the self-organising capability to form the whole organism. Embryonic stem (ES) cells are embryo-derived cell lines that retain pluripotency and represent invaluable tools for research into the mechanisms of tissue formation. Recently, murine fibroblasts have been reprogrammed directly to pluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and c-Myc) to yield induced pluripotent stem (iPS) cells.






 Oct4 (Octamer-binding transcription factor 4, also known as Oct 3 and Pou5f1) play a key role in the maintenance and self-renewal of pluripotent cells. Its expression is essential for the development of the inner cell mass(ICM) in vivo, the derivation of ES cells and the maintenance of a pluripotent state. The precise levels of Oct-3/4 govern three distinct fates of ES cells. Within a narrow window of expression, ES cells retain an undifferentiated, pluripotent state. A less than twofold increase in expression causes differentiation into primitive endoderm and mesoderm, whereas repression of Oct-3/4 induces loss of pluripotency and differentiation into trophectoderm.


 Sox2 (SRY-type high mobility group box2) is a transcriptional factor, which shares the HMG box DNA binding motif with numerous proteins. Down-regulation of Sox2 in mouse ES cell lines promotes differentiation into trophectoderm as well as other lineages, clearly demonstrating the importance of Sox2 in maintaining pluripotency. Sox2 regulatory elements frequently contain Oct3/4 and Nanog binding sites, and Sox2 acts in combination with Oct3/4 to regulate many genes in ES cells.


 c-Myc is a pleiotropic transcription factor that has been linked to several cellular functions, including cell-cycle regulation, proliferation, growth, differentiation and metabolism. c-Myc functions during both self-renewal and the differentiation of stem and progenitor cells, particularly in interactions between stem cells and the local microenvironment. 


 Klf4 (Krüppel-like factor 4) is a tranctiption factor expressed in a variety of tissues, including the epithelium of the intestine, kidney and the skin. Overexpreesion of Klf4 in ES cells inhibits differentiation in erythroid progenitors, and it co-operates with both Oct3/4 and Sox2 to activate the proximal promoters of a small number of target genes. Klf4 was shown to be dispensable in the maintenance of the undifferentiated state of mouse ES cells and that Krüppel-like factor(Klfs) are required for self-renewal of ES cells. In addition it was demonstrated that Klfs and Nanog share many common target genes and that Klfs regulated Nanog, indicating some integration between Klf and Nanog transcriptional circuitry.


 iPS cells generate all lineages of the embryo and contribute to chimera formation, so iPS cells have a developmental potency comparable to ES cells. Furthermore, iPS cells have already been differentiated into various functional cell types, including neurons, cardiomyocytes and hematopieitic cells. Using a combination of gene targeting and nuclear transfer, the combination of direct reprogramming and gene targeting can be used for therapeutic purpose in the mouse. The differentiated iPS cells could rescue the disease phenotype when transplanted into the donor mice. Similarly, Wernig and colleagues showed that iPS-cell-derived dopaminergic neurons could alleviate the disease phenotype in a rat model Parkinson’s disease. These murine expreriments suggest that, in principle human iPS cells could also be used for regenerative and therapeutic applications.