In the latest Nature Reports Stem Cells Inside the Paper feature, senior Nature editor Natalie DeWitt discusses the paper by H. H. Chang et al. ‘Transcriptome-wide noise controls lineage choice in mammalian progenitor cells’, published in Nature 453, 544-547 (2008).
The Editor’s summary of this paper: Even in clonal populations of cells, there is significant phenotypic variation from cell to cell. This could reflect the ‘noise’ inherent in gene expression: or the various cell states could represent stable phenotypic variants. Chang et al. analysed the behaviour of an ‘outlier’ in clonal populations of mouse haematoipoietic stem cells that had very high expressions of the stem cell marker Sca-1 and found that outliers possessed distinct transcriptomes. Though the transcriptomes eventually reverted back to that of the median cells, while they differed they could drive the cells to express characteristics of distinct cell fates. Thus clonal heterogeneity of gene expression may not be due to noise in the expression of individual genes, but rather is a manifestation of metastable states of a slowly fluctuating transcriptome. These fluctuations may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.
The Nature Reports Stem Cells article provides the details of what the peer-reviewers thought of this paper when it was submitted, and how the authors responded. The initial view of the three peer-reviewers can be summarized as follows:
Reviewer 1 In summary, we believe that this paper reports a novel and important biological mechanism for differentiation: it gives evidence that slow stochastic variations in stem cell state last for a long time and result in different fates. It relates the recent finding of slow fluctuations in human protein levels to the biological outcome of cell fate, and finds long lasting differences in transcriptomes in different subpopulations. It is an excellent choice for Nature, provided that the comments are addressed.
Reviewer 2 Although the phenomenon described is immensely interesting and the idea of heterogeneity being retained within even clonal populations of cells is plausible, the authors merely describe this phenomenon and in some instances, do not provide conclusive data to support their interpretation. If a mechanism was determined this would definitely aid in its novelty and interest. In its current form, I believe this manuscript should not be accepted at Nature.
Reviewer 3 This is a very timely and interesting paper, that should be of interest to a broad range of researchers. However, I have some serious concerns over the modeling.
The details of the reviewers’ concerns, and the authors’ response, can be read at Nature Reports Stem Cells,
You can also read a set of question-and-answer sessions between editor Monya Baker and several of the peer-reviewers of the recent Nature Insight on Regenerative Medicine, here on The Niche, the blog of Nature Reports Stem Cells.