(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