Embryonic stem cells can create copies of themselves, but can also mature into almost any type of cell in the body. Tiny gene regulators called microRNAs are now shown to have a role in directing these properties.
The single-celled, fertilized embryo is the source of all the trillions of specialized cells in our bodies, and the means by which this proliferation and specialization occur has fascinated developmental biologists for centuries. Moreover, the ability to artificially force mature, differentiated cells back into this naive state (called reprogramming) has huge potential in providing tools for regenerative medicine and for increasing our understanding of development. The work described on page 621 of this issue by Melton, Judson and Blelloch1 indicates that small RNAs have a crucial role in stem-cell biology and therefore in future stem-cell-based therapies.
The cells that form soon after fertilization — embryonic stem cells — have a remarkable ability to divide rapidly, to make copies of themselves (self-renew) and to differentiate into any type of specialized cell — a property known as pluripotency. Once cells have differentiated, they express a set of genes encoding factors that inhibit self-renewal and that seal the differentiated state. Our understanding of the nature of this switch between pluripotent and differentiated states is still rudimentary, but several important regulatory genes are known to be required for the process. Moreover, when artificially expressed in differentiated cells (for instance, skin cells), a subset of these regulatory genes, which encode proteins known as 'stemness' factors, can reprogram the cells back to the pluripotent state2,3, generating what are known as induced pluripotent stem cells (iPSCs). In an interesting convergence of research, multiple lines of evidence point to a type of RNA, called microRNA, as an essential factor in this switch.
MicroRNAs, as their name suggests, are tiny RNA molecules that are encoded in our genome. MicroRNAs are not translated into protein; their function is to regulate gene expression4 by binding to other RNAs, particularly messenger RNAs. Binding of microRNA to mRNA inhibits mRNA translation to protein. In humans, thousands of microRNAs regulate thousands of mRNAs in a complex network.
MicroRNAs were first discovered in the nematode worm Caenorhabditis elegans, when mutations in the microRNA genes lin-4 and let-7 were found to result in defective stem-cell maturation5,6. Specifically, in the absence of these genes, C. elegans epithelial stem cells known as seam cells failed to exit from the self-renewing state and to differentiate. Further work has revealed that microRNAs are involved in almost every biological process — including development, metabolism and ageing — in all multicellular organisms4. Moreover, microRNAs have been identified as being involved in many human diseases, most notably cancer7,8.
The let-7 microRNA is expressed in seam cells and mammalian stem cells9 just before the cells differentiate. Thus, it has been proposed that let-7 is a conserved anti-stemness and pro-differentiation factor. Its mechanism of action, however, had remained elusive. Melton et al. now demonstrate1 that let-7 is a key factor in inducing the differentiation of mouse embryonic stem cells, and it seems to be essential for depleting the cell of several stemness factors whose encoding genes and mRNAs are enriched in let-7 binding sites. Decreasing the amounts of these stemness factors promotes differentiation (Fig. 1). In addition, the authors identify another family of microRNAs that prevents let-7 from promoting differentiation. These findings form the basis of a model proposing that different types of microRNA have opposing effects on the fate of embryonic stem cells, one type promoting self-renewal and the other promoting differentiation.
In C. elegans, a mutation of the lin-28 gene results in premature differentiation of stem cells10, indicating that the LIN-28 protein is also a stemness factor. Recent work11,12,13,14,15 has shown that LIN-28 is an RNA-binding protein that inhibits the processing and maturation of let-7 microRNA in both mammals and C. elegans (microRNAs are modified by various proteins before they become fully functional). Moreover, LIN-28 is needed for efficient iPSC production2. If one 'joins the dots', it's not difficult to imagine that one of the roles of LIN-28 in iPSC production may be to suppress the maturation of let-7 microRNA16. The current work1 shows that inhibition of let-7 promotes iPSC production from mature cells, supporting this model and highlighting the importance of this microRNA in maintaining the differentiated state (Fig. 1).
Melton and colleagues' observations1 raise interesting prospects for regenerative medicine. First, they suggest that transient manipulation of microRNA levels might be a preferred route for generating iPSCs. The authors' findings will also interest workers in the cancer field, in which there is growing support for an emerging hypothesis that mutant stem cells are responsible for many cancers. The work1 surely reinforces the strategy of manipulating the amounts of such microRNAs in tumours as anticancer therapy. These smallest of RNA molecules seem to have a big future ahead.
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Slack, F. Big roles for small RNAs. Nature 463, 616 (2010). https://doi.org/10.1038/463616a
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