The stem cells are the basic cells of our bodiesthat have capacity to renew and multiply themselves indefinitely.
There aremainly two types of stem cells, embryonic stem cells (ESCs) and tissue-specific(adult) stem cells. ESCs can be isolated from the ICM of the blastocyst at day5 after fertilization. These cells can differentiate into any cell type of thebody given appropriate conditions, and proliferate infinitely as well. On theother hand, adult stem cells that reside in most tissues can only bedifferentiated into limited number of cell types of their tissue origin, andhave limited proliferation. The stem cells can be categorized into four groups,totipotent, pluripotent, multipotent and unipotent stem cells, based on itsdifferentiation potency.
Totipotent stem cells are the cells of embryo fromfertilized egg stage to the eight-cell stage, which can differentiate into bothembryonic and extraembryonic cell types. Pluripotent stem cells are the cellsof inner cell mass of the blastocyst that can differentiate into all embryonictissue except extraembryonic tissues. Multipotent stem cells are the cells thatdifferentiate into different types of cells but limited to its specific celllineage such as endoderm, ectoderm and mesoderm. Unipotent stem cells are thecells with no pluripotency but self-renewal characteristic that differentiateinto only one type of cell such as adult stem cells. Thefirst derivation of human embryonic stem cells (hESCs) in 1998 has introduced thepotential application of pluripotent and self-renewal characteristics of stemcells in various area of scientific research, and has been provided as a toolfor studying human developmental processes, modeling diseases and drugscreening. However, derivation process of hESCs raised ethical concerns aboutdestroying human embryos. Moreover, use of hESCs for future clinicalapplication required life-long administration of immunosuppressive drugs.
Theselimitations of hESCs were overcome by discovery of patient-specific inducedplruipotent stem cells (iPSCs). In2006, induced pluripotent stem cells (iPSCs) were discovered by Takahashi andYamanaka through reprogramming mouse skin cells. IPSCs resembled thecharacteristics of self-renewal and pluripotency of hESCs. IPSCs were generatedfrom adult somatic cells by introducing specific transcriptional factors,called Yamanaka factors, which induce changes in epigenetic conformation anddifferentiation potential of the cells (Matthias). The factors reactivate dormantpluripotency genes. Yamanaka and Takahashi identified a set of fourtranscriptional factors, c-Myc, Oct3/4, SOX2 and Klf4, among 24 factors thatactivate the pluripotency gene, Fbxo15 locus.
This set of transcriptionalfactors are introduced using retrovirus-mediated transduction and successfullyreactivated the Fbxo15 gene, reprogramming the fibroblast into iPSCs, however,the resultant iPSCs showed incomplete promoter demethylation of embryonic stemcell (ESC) regulators such as OCT4, and failed to differentiate into three germlines, thus expressing lower pluripotency compared with ESCs. Therefore, toincrease the level of pluripotency, another pluripotency gene, Nanog, isselected and reactivated instead of Fbxo15, which resulted generation of iPSCsthat molecularly and functionally more resembles ESCs (Maherali). With thisimplemented pluripotency gene, in 2007, the first human induced pluripotentstem cells (hiPSCs) are generated from human fibroblasts by introducing acocktail of transcriptional factors, Oct3/4, SOX2, Nanog and Lin28, with thesame method used in reprogramming of mouse fibroblast.