Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR.
MicroRNA-mediated conversion of human fibroblasts to neurons.
Nature. 2011 Aug 11;476(7359):228-31.
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Cell reprogramming has been generally promoted using "master regulators," meaning those
genes coding for transcription factors that act during embryogenesis as cell lineage-specific
determinants. In other words, only those transcription factors known to promote a specific
cell fate have been used for inducing cell reprogramming.
Now, Gerald Crabtree and colleagues show that an miRNA might function similarly to "master regulators" in reprogramming cell fate, and, in particular, to sustain the conversion of fibroblasts
directly into neurons. Despite our knowledge on the pleiotropic functions played by miRNAs in all
biological processes, this is a meaningful example that directly proves how powerful these molecules are in directing cellular identity. Indeed, overexpression of two miRNAs, miR9-9* and miR-124, is able
to promote this cell conversion in human cells. However, the efficiency is very low (Combining miRNAs with master genes might be the right way to produce high numbers of human cell types
with a relevant clinical interest, as, for instance, specific neuronal classes.
In this article, Yoo and colleagues present the interesting finding that microRNAs (-9* and -124) have some neurogenic effects. Together with NeuroD2, Ascl1, and Myt1l, microRNAs (-9* and -124) convert human fibroblasts into functional neurons. In addition to two papers from other groups published in Nature (1) and PNAS (2), this study adds more proof for the principle that a direct conversion of human neurons from fibroblasts is possible, which we proposed in our recent study (3). Compared to the factors we use (Brn2, Ascl1, Myt1l, and NeuroD1) to induce human neurons, the inducing factors Yoo and his colleagues report are remarkably similar, since three transcription factors are essentially the same (the helix-loop-helix domain of NeuroD1 and NeuroD2 is highly conserved). Thus, at first glance, it would appear that the neurogenic properties of these two microRNAs are similar to those of Brn2. However, comparing conversion efficiencies is difficult since one has to correct for proliferation and, more importantly, it is still unclear what particular neuronal subtype is generated by forced expression of these factors, and it might well be that microRNAs and Brn2 direct cells toward different neuronal fates. Further characterization of the neuronal markers expressed in these neurons is needed prior to addressing these questions. Yoo and colleagues' study highlights microRNAs as potentially important factors that might help in deriving specific neuronal subtypes.
One additional note, as we reported, the human neurons from these studies seem relatively immature, given their low competency in synaptic formation and functioning. Obviously, future studies are necessary to thoroughly optimize conditions for human induced neuronal cell generation and maturation.
Caiazzo M, Dell'anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov RR, Gustincich S, Dityatev A, Broccoli V.
Direct generation of functional dopaminergic neurons from mouse and human fibroblasts.
Nature. 2011 Aug 11;476(7359):224-7.
Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M.
Direct conversion of human fibroblasts to dopaminergic neurons.
Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10343-8.
Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC, Wernig M.
Induction of human neuronal cells by defined transcription factors.
Nature. 2011 Aug 11;476(7359):220-3.
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