Algorithm indicates Nanog protein autorepression regulates stem cell self-renewal
Collaborative research between Helmholtz Zentrum München (Neuherberg, Germany), Technical University of Munich (Maxvorstadt, Germany) and ETH Zürich (Switzerland) has used algorithm software and time-lapse fluorescence microscopy data to provide evidence that Nanog is regulated by a negative-feedback loop.
Nanog is a heterogeneously expressed core pluripotency factor critical protein for stem cell renewal, but how the quantity of Nanog in the cell is regulated has been debated. Some scientists believed that Nanog activates itself in order to preserve the pluripotency in embryonic stem cells, but a team of researchers including Dr Carsten Marr, head of the Quantitative Single Cell Dynamics research group at the Helmholtz Zentrum München (Neuherberg, Germany), refutes this hypothesis.
Together with colleagues from ETH Zürich (Switzerland) and the Technical University of Munich (Maxvorstadt, Germany), the team developed an algorithm called Stochastic Inference on Lineage Trees, or STILT, which is freely available to other scientists online, to evaluate time-resolved Nanog protein expression data (already collected in 2015) from individual mouse stem cells via fluorescence imaging.
“We compared the Nanog dynamics that were measured in this way with three different models. One of the challenges here was the quantitative comparison of the models, and another was taking stem cell divisions into account in the algorithm,” reports first author Dr Justin Feigelman, who had moved from the Helmholtz Zentrum München to ETH Zürich as a postdoc. “The results show that Nanog is regulated by a so-called negative feedback loop, which means that the more Nanog there is in the cells, the less reproduction there will be.”
The scientists validated this result by calculating the results of an artificial increase in Nanog protein levels. “We then actually succeeded in confirming the hypothesis put forward by STILT in an additional single-cell experiment with increased Nanog,” stated study leader Marr, who works at the Helmholtz Institute of Computational Biology.
The scientists believe that this research, and the improved knowledge on stem cell renewal that it should provide, will support future medical applications. Marr commented: “We will also be applying STILT to other time-resolved single cell data in the future, which will give us insight into the underlying molecular gene regulation mechanisms.”
Sources: Feigelman J, Ganscha S, Hastreiter S et al. Analysis of cell lineage trees by exact Bayesian inference identifies negative autoregulation of Nanog in mouse embryonic stem cells. Cell Syst. 3(5), 480–490 (2016); https://www.helmholtz-muenchen.de/en/news/latest-news/press-information-news/article/36612/index.html