Stem cells need to stick together

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(Stem Cells, Sep 2012) Researchers began dissecting the molecular pathways that help stem cells remain undifferentiated when properly bound to each other.
During the last several years there has been tremendous progress in our understanding of the autonomous mediating in stem cells. Comparatively, less is known about how stem cells are regulated by higher levels of tissue organization, such as intercellular interactions.
Kate Hawkins and a group of collaborators led by Christopher Ward at the University of Manchester, have recently begun a more careful dissection of the pathway that connects the binding between cells through proteins called cadherins and the expression of key pluripotency regulators in mouse embryonic stem cells (or ). In their recent Stem Cell article (1), this research team presents evidence for an unexpected regulatory switch that allows mESCs lacking the cell-cell binding protein E-cadherin to remain pluripotent.
Through an initial set of experiments, Hawkins and colleagues found that the binding of stem cells that express E-cadherin molecules on their surface leads to the activation of another intracellular protein called , which in turn induces the expression of the pluripotency factors . Stem cells without an E-cadherin gene, on the other hand, fail to activate STAT3 and express much reduced levels of Klf4 and Nanog. However, mESCs remained pluripotent and could still turn on the expression of Klf4 and Nanog when their culture media was supplemented with a compound called Leukemia Inhibitory Factor (or LIF). Normal cells crank up the production of Klf4 and Nanog like gangbusters when they are exposed to LIF in the media, while E-cadherin mutant cells showed an attenuated response. But there was a response nonetheless.
This observation may have seemed to undermine a requirement for stem cells to bind each other in order to remain pluripotent. However, Ward’s team also observed that the E-cadherin mutant cells exposed to LIF turn on the expression of the closely related cell adhesion gene N-cadherin, restoring STAT3 activation when cells stick together. Perhaps more interestingly, unlike E-cadherin mutant cells, normal cells do not express N-cadherin in response to LIF, suggesting a significant and intriguing rewiring of the genetic regulatory network in cells that lack E-cadherin.
The findings by Hawkins and colleagues serve as an interesting example of how stem cells can switch between regulatory landscapes, and a humbling reminder of the challenges that scientists face in the pursuit of a unifying model of stem cell regulation.

(1) Hawkins K et al. E-cadherin and, in its absence, N-cadherin promotes Nanog expression in mouse Embryonic Stem Cells via STAT3 phosphorylation. Stem Cells. 2012 Sep;30(9):1842-51. doi: 10.1002/stem.1148

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Some genes (called transcription factors) bind to other genes in DNA and affect their expression. When these so-called target genes are transcription factors themselves, they will in turn affect the expression of many other genes, some of which may be transcription factors… and so on. This phenomenon gives rise to what biologists call transcriptional regulatory networks, meaning networks of genes that can affect the expression of hundreds, if not thousands of other genes in a cell.
In developmental biology, ‘pluripotency’ refers to the potential of a precursor cell to differentiate into multiple different cell types. Some stem cells are programmed to give rise to a very limited number of cell types, but pluripotent stem cells can in principle generate most cell types in the organism.
mESCs are very commonly used in stem cell research labs, because they are an archetypical pluripotent stem cell (they can generate most mouse cell types if correctly instructed to do so) and they are relatively easier to obtain, mantain and manipulate than other stem cells.
STAT3 is short for Signal Transducer and Activator of Transcription 3. This protein gets activated at the cell membrane in response to several different signals (in this particular case, cells binding to each other through E-cadherin). Once activated, STAT proteins enter the nucleus and function as a transcription factor, generally activating the expression of target genes.
Klf4 and Nanog are dubbed pluripotency factors because, without them, stem cells cannot remain pluripotent (ie. they spontaneously differentiate).
When researchers say that a given cell or organism is ‘mutant’ for a gene, they mean that the gene is abnormal. But ‘mutant’ is a rather broad term, because ‘gene X mutant’ can equally refer to the absence, to the alteration or to the hyperactivation of gene X. In this case, E-cadherin mutant cells refers to cells that lack the E-cadherin gene.

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