Two reports in the September 12 SciencExpress take advantage of gene chip technology to show broad pictures of how stem cells are different from differentiated cells at the genomic level.
Douglas Melton, Miguel Ramalho-Santos, and colleagues at Harvard University compared the gene expression profiles of mouse embryonic, neural, and hematopoietic stem cells. On average, each of the three stem cell types had a pattern of more than 2,000 genes whose mRNAs were highly enriched compared to differentiated control cells. However, only 216 of those genes were common to all three stem cells. This latter observation casts doubt on recent suggestions that different classes of stem cell types might be quite similar at the transcriptional level.
One interesting characteristic of the 216 genes shared among the different types of stem cells is that they contained a much higher percentage of "mystery" genes, whose functions are unknown, than was found among the differentiated cells. The authors also noted that only four genes-Uridine phosphorylase, Suppressor of Lec15 and two expressed sequence tags-were present in all 3 stem cell types and absent in all the differentiated control cells.
Based on their analysis of the genes whose functions are already known or suspected, the authors suggest that the core properties of stem cells include: (i) active Jak/Stat, TGF-β, Yes-kinase and Notch signaling; (ii) the capacity to sense growth hormone and thrombin; (iii) interaction with the extracellular matrix via integrin α6/β1, Adam9 and Bystin; (iv) engagement in the cell cycle, either arrested in G1 or cycling; (v) high resistance to stress, with up-regulated DNA repair, protein folding, ubiquitin system and detoxifier systems; (vi) a remodeled chromatin, shaped by DNA helicases, DNA methylases and histone deacetylases; and (vii) translation regulated by RNA helicases of the Vasa type. Some of these characteristics resemble those of cells under stress, note the authors. (Annotated lists of the genes enriched in these cells, as well as other supporting materials are at www.sciencemag.org/cgi/content/full/1072530/DC1)
The results indicated that the greatest degree of overlap is between embryonic stem cells and neural stem cells. Hematopoietic stem cells were actually closer in profile to adult bone marrow cells than to the other two stem cell populations. Supporting the assay’s validity, this study replicated most gene products previously shown to be enriched in particular populations of stem cells.
In a parallel study, Ihor Lemischka, Natalia Ivanova and colleagues at Princeton University in New Jersey find similar numbers with similar techniques: more than 2,000 enriched genes in each stem cell population, 283 of which were common to neural, embryonic, hematopoietic stem cells. Among these, the authors point to several transcription factors-Edr1, Tcf3, EfnB2, and Hes1-which have already been implicated in the regulation of one or more stem cell types. (Complete data sets and other supporting material are at www.sciencemag.org/cgi/content/full/1073823/DC1.)
These authors also compared mouse and human hematopoietic stem cells, finding 822 human homologues for genes upregulated in mouse hematopoietic stem cells. Among these, 322 were also enriched in human hematopoietic stem cells. Lemischka et al focus much of their attention on the hematopoietic hierarchy, which begins with an omnipotent stem cell and passes through several stages of progressively more restricted progenitor cells that ultimately give rise to at least ten different types of blood cell. They found that 45 percent of the genes specific to the early, more potent cells coded for regulatory molecules such as transcription factors, intracellular signaling proteins, and cell surface receptors and ligands.
"It is likely that hallmark properties shared by all [stems cells], such as the ability to balance self-renewal and differentiation will be governed by shared molecular mechanisms. As such, numerous components of these molecular mechanisms are likely to be contained within the [stem cells] molecular signature presented here," conclude Lemischka et al.—Hakon Heimer
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- Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science. 2002 Oct 18;298(5593):601-4. PubMed.
- Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA. "Stemness": transcriptional profiling of embryonic and adult stem cells. Science. 2002 Oct 18;298(5593):597-600. PubMed.