The role of circular RNAs in stem cell differentiation
The role of circular RNAs in stem cell differentiation
Roqaye Karimi,1,*Amir Atashi,2Monireh Ajami,3Mansoureh Ajami,4
1. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran 2. Stem cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran 3. Department of Medical Laboratory Sciences, School of Paramedical Sciences, Islamic Azad University Tehran Medical Sciences, Tehran, Iran 4. Department of hematology, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
Introduction: Stem cells are the primary cells that have the ability to differentiate into various types of cells, and it has been proven that stem cells can treat a number of different diseases. Some of the most important applications of stem cells include the repair of damaged heart tissue, bone tissue repair, treatment of nerve and spinal cord injuries, treatment of diabetes, etc. New strategies are needed for stem cell differentiation, one of which is the use of circular RNAs (circRNAs). circRNAs are a group of non-coding RNAs (ncRNAs) that are produced from protein encoding genes through a process called back splicing and are resistant to mRNA-degrading enzymes due to their their circular structure and lack of a 5' cap and a poly-A tail. This resistance has caused circRNAs to have relatively longer stability and half-lives than their linear counterparts and other ncRNAs, including miRNA and LncRNAs, making them potential tools for therapeutic innovative strategies. In general, circRNAs are expressed in eukaryotes and have tissue-/cell-specific patterns. Many studies have suggested that circRNAs play an essential role in important cellular processes, such as evolution and differentiation through post-translational regulation, and their expression disorder is involved in the pathogenesis of a variety of diseases. Along with the development of bioinformatics technology, several circRNAs with important biological functions have been discovered. They act as sponges for miRNAs and subsequently play a major role in regulating stem cell differentiation by regulating the function of miRNAs through their spongy activity. As stem cells are differentiated into mature cells such as neuronal differentiation, myocardial differentiation and osteogenic differentiation, the expression of some circRNAs increases significantly, indicating the importance of circRNAs as biomarkers of stem cell differentiation and a new pathway for stem cell-based therapy.
Methods: We reviewed and analyzed a large number of scientific papers related to the role of circRNAs in stem cell differentiation and the relationship between circRNA and miRNA expression in the differentiation of these cells. Microarray analysis technique was used to identify the expression profile of circRNAs during the stem cell differentiation. qRT-PCR was used to detect circRNA expression. The function of circRNAs was evaluated by gain- and loss-of-function experiments. Using bioinformatics analysis tools, circRNA-miRNA binding sites, and the target genes of miRNA, were identified.
Results: Several regulatory axes including circ_33287/miR-214-3p/Runx3, circ_0074834/miR-942-5p/VEGF and ZEB1, circ_124534/miR-496/β-catenin, circ_ARHGAP35-circ_2929/miR-204-5p/Runx2 and circ_ITCH-circ_BANP/miR-34a/DUSP1, RAC1 and FAS were identified as essential players in osteogenic stem cell differentiation and bone regeneration. On the other hand, circCACNA1D, circSLC8A1, and circALPK2 played a crucial role in the process of cardiac differentiation of stem cells, and circRIMS2, circRTN4, and CDR1as were involved in the process of neural differentiation of stem cells as well.
Conclusion: To sum up, circRNAs and stem cells have emerged as a novel filed of research. There is ample evidence that the expression of large numbers of circRNAs will change during stem cell differentiation, and several circRNAs play a key role in regulating the differentiation of different stem cell types. Regarding the interaction of circRNAs with miRNAs and their impact on target genes, the identification of circRNA-miRNA-mRNA network has been considered by many researchers today. The impact of miRNAs on the target genes’ expression level can be targeted by the spongy effect of specific circRNAs. Exosomes or nanoparticles are recently used as the systems for delivering these molecules into cells. Furthermore, the CRISPR/Cas13 technology and the cre/lox system are used for knocking down circRNAs in stem cells to differentiate them and to develop therapies based on circRNAs. Overall, the circRNAs-miRNAs network plays a major role in regulating stem cell differentiation, which might be a potential new target for the treatment of diseases and suggest the possibility of targeted circRNA therapies in tissue engineering.