Eleven years ago Takahashi and Yamanaka brought to light a breakthrough in the history of stem cells biology They were able to create induced pluripotent stem cells iPSCs originated from mouse fibroblasts by expressing on them four embryonic transcription factors Oct4 Sox2 Klf4 and c Myc which are known as Yamanaka factors 1 The most important characteristic about iPS cells is that they share a high level of resemblance with embryonic stem cells regarding to their morphology the genes they express the way they differentiate and the epigenetic patterns that they acquire both in vitro and in vivo 2 Ever since human iPSC technology has been undoubtedly proven to be a very promising aspect of Regenerative Medicine and Pharmaceutical Industry since they can be used in stem cell based therapies human disease modeling and drug discovery 3 The reason of efficacy of this technology in aforementioned approaches is the fact that iPSCs are derived from the same person autologous cells in which they are to be used as a treatment or as a medium for drug screening Therefore the risk of rejection of the treatment by the immune system of the patient is limited Moreover iPSCs technology has eliminated any kind of conflicts in modern society regarding their use by replacing the use of human embryonic stem cells hESCs in respective approaches 4 However there seem to be some limitations regarding iPSC technology and one of them is the low reprogramming efficiency of iPS cells 5 This low efficiency is connected to a phenomenon called epigenetic memory which refers to residual epigenetic signatures of the somatic tissue of origin 6 Furthermore reprogramming process can also lead to complete alteration of the pre existing somatic epigenetic memory and to the creation of a new epigenetic signature that is indicative of the upcoming differentiated cell type Consequently the epigenetic memory phenomenon consists an obstacle that needs to be overcome for a more effective iPS reprogramming 7 Epigenetics and iPSCs The term Epigenetics refers to the interaction between our genetic material and the environment through the developmental process It includes any reversible and inheritable change in the functional genome that does not affect the DNA sequence 8 Although exogenously introduced transcription factors are responsible for the iPSC reprogramming epigenetic alterations such as DNA methylation can influence the progress and the efficiency of the transition to pluripotency Epigenetic changes during iPSC reprogramming DNA methylation
This epigenetic modification is considered to be an important obstacle in the reprogramming of induced pluripotent cells 9 A sufficient reprogramming requires demethylation of cytosines in the promoter regions of genes Such genes are Oct3 4 and Nanog which are really important for this process Therefore by inhibiting the methylation procedure an amelioration of this process can be achieved This inhibition can be conducted by enzymes or RNAi method 10 Histone modifications Histone modifications can alter the level of folding of chromatin which means that they are responsible for the active inactive stage of chromatin and therefore for gene expression itself 11 12 The histone which is mostly epigenetically modificated is H3 and the most common type of methylation is H3K27me3 which inhibits the process of reprogramming by suppressing regions of chromatin that are related with the expression of many embryonic genes such as Oct3 4 Sox2 and Nanog 13 In order to achieve a complete reprogramming of iPSCs the effect of epigenetic memory in the cells of the somatic tissue of origin must be minimized Many attempts have been conducted by the researchers and they claim that they can induce pluripotency without using the already known and widely used Yamanaka factors
They suggest that pluripotency can be achieved simply by using some specific chemical compounds that interact with enzymes who regulate the structure of chromatin 14 15 Also in another study some researchers demonstrated that the prohibition of a subunit of NuRD Nucleosome Remodeling Deacetylase complex which normally deacetylates histones remodels nucleosomes and suppresses gene expression can reactivate embryonic genes and ameliorate the effectiveness of iPSC reprogramming by 90 Hence by using chromatin modulators an increase in the adequacy of reprogrammed iPSCs can be achieved 16 miRNAs miRNAs are really important molecules that regulate gene expression in post transcriptional level In the case of iPSCs miRNAs promote their pluripotency by destabilizing specific mRNAs and suppressing signs of differentiation amid the self renewal Moreover miRNAs regulate signaling cascades which are crucial for the pluripotency stage Researchers have found that the loss of function of proteins Dicer and DGCR8 important for the generation of miRNAs in mouse ESCs resulted in less proliferation rate due to cell cycle arrest in G1 phase and in maintenance to differentiation state Thus there is a strong correlation between miRNAs differentiation and pluripotency stages Finally miRNAs can be used as tools in the intervention of iPSC reprogramming in the absence of ectopic expression of Yamanaka factors 17 18
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