Molecular basis of reprogramming: Modulation by microRNAs

Abstract

Induced pluripotent stem cells (iPSCs) have opened up a new avenue for customized regenerative medicine. iPSCs can be generated by forced expression of transcription factors, Oct4, Sox2, c-Myc and KIf4. Although reprogramming techniques are well documented, one of the major concerns has been the poor efficiency of reprogramming. The reprogramming efficiency can be enhanced using various chemical compounds and vector systems. However, low reprogramming efficiencies and use of viral based vector systems limit clinical application of iPSCs. microRNAs (miRNAs) are extensively studied due to their critical role in numerous biological activities like cell cycle regulation, growth control and apoptosis. Discovery of embryonic stem cell (ESC) specific unique miRNAs, encouraged researchers to study contribution of miRNAs towards embryonic stem cell development, differentiation and somatic cell reprogramming (SCR). Depletion of mouse embryonic fibroblast (MEF) enriched miRNAs like miR-29a, miR-21 and let-7, are necessary to enhance reprogramming. Furthermore, up regulation of miR-200, miR-106a/b miR-120, miR-93 miR-301, miR-17, miR-721, miR-29b is required for mesenchymal-to-epithelial transition (MET), a critical initial event during the generation of iPSCs from fibroblasts. The expression of embryonic stem cell specific miRNAs like miR-290/miR-302 cluster, miR-367/miR372 is crucial to maintain pluripotent status of iPSCs. In this review, we discuss contribution of miRNAs to generation of iPSCs, their defined role in maintenance of pluripotent state, transcriptional regulatory networks and epigenetic factors to modulate reprogramming.