In Stem Cells

miRNAs can form extensive regulatory networks with a complexity comparable to that of transcription factor [37]. miRNA pathways have been defined in timing development in C. elegans such as lin4 and let 7. A recent study has shown that let-7 inhibits Ras activity in human lung cancer [38]. miRNA-mediated signal transduction pathways in stem cells has been proposed recently. Shcherbata et al. [39] hypothesized that the environmental regulation of Drosophila GSC division could act through miRNA-dependent regulation of P21/P27 /Dacapo. When the conditions are unfavorable for division, the key miRNAs are down-regulated, resulting in an increased p21/p27/Dacapo level, which subsequently halts the cell cycle in G1/S (Figure 2). We have suggested recently an optimal ratio between serine and tyrosine phosphorylation of STAT3 is a key condition to keep mouse ES cell pluripotency [40]. Activation of STAT3 also plays an important role in neuronal development, particularly in inhibiting neuronal terminal differentiation from neuronal stem cells [41, 42]. In mouse ES cell-derived neural precursors, miR-9 and miR-124a act in the STAT3 signaling pathway through phosphorylation of STAT3 protein without affecting the mRNA and protein level. MiR-9 inhibit STAT3 Tyr705 phosphorylation in those neural precursors [36] (Figure 2). Currently, there is no ample evidence showing miRNA posttranslationally regulated targets, one possible explanation might be indirect effect of miR-9 on STAT3. Both miR-221 and miR-222 affect c-Kit expression in human umbilical vein endothelial cells ; as a consequence, they affect the angiogenic properties of stem cell factor, the ligand of c-Kit. Interaction between miR-222 and c-Kit is likely to be part of a complex circuit that controls the ability of endothelial cells to form new capillaries [43]. Since SCF-Kit signaling pathway plays an important role as a survival factor for many type of stem/progenitor cells, including hematopoietic stem cell and neuronal stem cells [44], one can speculate that miRNA regulate stem cell survival via regulation of c-Kit signaling. miR-223 was identified as an important modulator of human myeloid differentiation. Interestingly, NF1-A inhibits miR-223 expression in undifferentiated progenitor cells, whereas c/EBPa binds the promoter of miR-223 in replacement of NF1-A and stimulates miR-223 expression during differentiation [32]. Gene regulation in stem cells are comprehensive, the regulatory circuitry between miRNAs and target genes appears crucial, however, new miRNA pathways remain to be uncovered in the future.

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