Regenerative medicine using spluripotent/multipotent stem cells holds a great promise in

Regenerative medicine using spluripotent/multipotent stem cells holds a great promise in developing therapies for treating developmental abnormalities, degenerative disorders, and aging-related illness. miR-302, induces somatic cell reprogramming (SCR) to form iPSCs, suggesting its pivotal role in stem cell generation. Recent research further revealed that miR-302-induced SCR entails an epigenetic reprogramming mechanism comparable to the natural zygotic reprogramming process in the two- to eight-cell-stage embryos. These findings show that miR-302, as a cytoplasmic gene silencer, inhibits the translation of multiple important epigenetic regulators, including AOF1/2, methyl-CpG binding proteins 1 and 2, and DNA (cytosine-5-)-methyltransferase 1, to induce global DNA demethylation, which subsequently causes the activation of the previously defined factors 125973-56-0 supplier Oct4, Sox2, and Nanog to total the reprogramming process. The same mechanism was also found in the event of somatic cell nuclear transfer. Based on these advanced understandings, this review explains the currently established SCR mechanismas compared to the natural process of early ESC formationand demonstrates how stem cell experts may use this mechanism to improve iPSC generation. Keywords: Induced pluripotent stem cell, Mechanism, Somatic cell reprogramming, DNA demethylation, Pluripotency, miR-302, microRNA In the past, it was widely thought that a stem cell, once differentiated, could not revert back to an earlier developmental stage. The recent finding of iPSCs, however, revokes this concept and provides the first evidence that there is usually an internal mechanism capable of reprogramming the stemness of a differentiated tissue cell back to an ESC-like pluripotent state, indicating a fountain of youth intrinsic to every cell in the body. A stem cell has two principal abilities of stemness: (1) self-renewal in which it can multiply through unlimited division and (2) pluripotency in which it can differentiate into a variety of tissue cells originating from all three embryonic germ layers, the ectoderm, mesoderm, and endoderm. The breakthrough finding of such a reprogramming event provides us a powerful means to generate and regenerate unlimited pluripotent stem cells directly from the practical pool of body tissue cells. Yet, the involved mechanism, called somatic cell reprogramming (SCR), remains evasive. SCR was first observed by transferring somatic cell nuclei into the cytoplasm of oocytes, which forms ESC-like hybrid cells that can develop into animal clones possessing the same genetic characteristics as the hosts of the somatic cell nuclei [1, 2]. Although this kind of somatic cell nuclear transfer (SCNT) technology has been intensively used for over 14 years to produce numerous species of animal clones, the necessity of oocytes is usually ethically controversial and the mechanism is usually ambiguous. In 2006, Takahashi and Yamanaka established a novel reprogramming method that bypassed any use of oocyte or embryonic components. By introducing four defined transcription factors, Oct4, Sox2, Klf4, and c-Myc, somatic cells were reprogrammed to iPSCs that showed ESC-like properties in almost all aspects [3]. Subsequently, Yu et al. [4] also successfully generated iPSCs using another set of four defined factors, Oct4, Sox2, Nanog, and Lin28. Nevertheless, with all these efforts, the SCR mechanism is usually still unsolved. It was not until 2 years after the finding of iPSCs when another method of iPSC generation was found which revealed the mechanism of SCR. Lin et al. and their peers showed that a small noncoding RNA, called miR-302, can replace all previously 125973-56-0 supplier defined factors to reprogram human and mouse somatic cells to ESC-like iPSCs [5C8]. It was understood that none of these human Rabbit Polyclonal to OPN5 iPSCs induced by miR-302 have been tested for germline transmission in either chimera or clones because of strong ethical issues. MiR-302 is usually a 23-ribonucleotide microRNA (miRNA) expressed abundantly in human ESCs but is usually absent in all differentiated tissue cells [9]. Despite its presence in ESCs, how does a small RNA, incapable of encoding any protein or peptide, play such a pivotal role in regulating SCR? 125973-56-0 supplier It converts out that miR-302 functions as a gene silencer and simultaneously downregulates multiple important epigenetic regulators, including lysine-specific histone demethylases 1 and 2 (namely AOF2/1, LSD1/2, or KDM1/1B), DNA (cytosine-5-)-methyltransferase 1 (DNMT1), and methyl-CpG binding.