MicroRNAs in regulation of pluripotency and somatic cell reprogramming: small molecule with big impact

Abstract

MicroRNAs (miRNAs), a group of small non-coding RNAs, have emerged as significant modulators in the establishment and generation of pluripotency, a developmental process that consists of complex cell-fate arrangements. The finding of embryonic stem cell (ESC) cycle-specific miRNAs reveals an important regulation scheme of pluripotency. Subsequent studies showed the ESC-enriched or ESC-depleted miRNAs can regulate induced pluripotent stem cells(iPSC). Moreover, miRNA profiling of iPSC and ESC may distinguish them from one another and facilitate the complex of regulatory network. The accumulative effects of miRNA action enable using miRNA alone to generate iPSCs. Despite the robustness of iPSC studies, further investigations are needed since miRNA may have more impact on induced pluripotency, and the roles of miRNAs in somatic cell nuclear transfer (SCNT), another approach toward cellular reprogramming, remains unclear. This point-of-view article will discuss miRNAs and their impact on the normal and induced pluripotency, as well as bring new insights on somatic cell reprogramming.

Keywords: MicroRNAs; embryonic stem cells; induced pluripotent stem cells; pluripotency regulation; regenerative medicine; somatic cell nuclear transfer; somatic cell reprogramming.

Figure 1. Routes to somatic cell reprogramming. (A) In conventional somatic nuclear transfer, the nucleus of an egg is removed and then the nucleus of a somatic adult cell is transplanted into the enucleated egg. The reconstructed embryo is culture into the blastocyst stage and nuclear transferred embryonic stem cells (NT-ESC) can be derived from the inner cell mass(ICM) of the blastocyst. The miRNA function during SCNT needs further investigations. (B) Transduction of pluripotent factors, namely Oct4, Nanog, Myc, and Klf, known as Yamanaka factors, into somatic adult cells can generate iPSCs. Successful iPSC generation and maintenance require the regulation of miRNAs. (C) Using miRNA only can generate iPSC successfully. miRNAs can induce somatic cell reprogramming alone in the absence of exogenous pluripotent factors.

Figure 2. Roles of miRNA in the regulation of iPSC. By suppressing TGF-β receptor-2, ESCC miRNAs can promote the early stage of somatic cell reprogramming, known as MET. miRNa involvement and the later stage of reprogramming remains unclear. ESCC miRNAs also target pluripotent genes and enhance induced reprogramming. On the other hand, Let-7 provides a barrier for somatic cell reprogramming and the inhibition of let-7 can result in pluripotency. By targeting p53, miR-34 family inhibits pluripotent genes; namely Nanog, Sox2, and N-Myc, and suppress adult cell reprogramming. Using miRNA (miR-200c, miR-302, miR-369) only can also induce reprogramming.