Deceptive Model: Stem Cells of Humans and Mice Differ More Strongly Than Suspected
ScienceDaily (Mar. 9, 2010) — They are considered to be the most important model organism for research into human biology: mice may look totally different, but they are in many ways similar to Homo sapiens on a fundamental level. For instance, an impressive 99 per cent of the mouse genes are matched by a corresponding sequence in the human genome. That is also why the law in this part of the world only permits scientists to conduct research on human embryo stem cells when they have "clarified in advance" their specific questions by using animal cells as far as possible.
Neural differentiation of mouse epiblast stem cells by inactivating the FGF signalling pathway. Molecular mechanisms to differentiate human and mouse stem cells may be similar but may also vary substantially on occasion. (Credit: Boris Greber)
For years scientists have puzzled over to what extent the findings of studies on the embryonic stem cells (ES cells) of mice are transferable to humans. It is certainly true that human and mouse ES cells are both pluripotent. That means they are capable of forming any of the body's cell types, numbering more than 200 in all. And both types of cells have an active Oct4 transcription factor, for example. This is the gene that is essential for maintaining pluripotency, and is what makes egg cells, as well as embryonic stem cells and early embryos, potentially immortal.
In other aspects, though, as scientists have known for some time now, human and mouse ES cells differ enormously. Certain signalling substances that can be used to turn mouse cells into liver, nerve or muscle cells, for instance, produce either no effect or totally different effects in human ES cells.
The reasons for this are still uncertain. However, in 2007 two research teams succeeded in isolating a promising new type of pluripotent cells from mice embryos (see Brons et al., Nature 448, 2007). Known as epiblast stem cells (EpiSC), these cells are also pluripotent. However, they stem from a later stage of embryonic development: unlike 'traditional' ES cells, which are harvested from a few-days-old embryo in the blastocyst stage, these are harvested from an embryo that has just lodged itself in the uterus and which is referred to as an epiblast.
The astonishing thing about it is that although epiblast stem cells are actually a step ahead in their development, they appear to be more similar to human ES cells than 'classic' mouse ES cells are. For example, both epiblast stem cells and human ES cells can, with the addition of a certain hormone, the FGF2 growth factor, be grown and held in a state in which they can turn into any tissue at all. "Epiblast stem cells from mice are therefore more-or-less equated with human ES cells in the general scientific discussion," says Boris Greber, the lead author of the study.
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Cell Stem Cell, Volume 6, Issue 3, 215-226, 5 March 2010 | Copyright © 2010 Elsevier Inc. All rights reserved. | 10.1016/j.stem.2010.01.003
Conserved and Divergent Roles of FGF Signaling in Mouse Epiblast Stem Cells and Human Embryonic Stem Cells
Boris Greber, Guangming Wu, Christof Bernemann, in Young Joo, Dong Wook Han, Kinarm Ko, Natalia Tapia, Davood Sabour, Jared Sterneckert, Paul Tesar, Hans R. Schöler
Nanog is a direct target of Activin and SMAD2/3 but not FGF-ERK in EpiSCs
FGF signaling inhibits neuroectodermal commitment of EpiSCs and hESCs
FGF inhibition relieves Klf2 repression and reverts EpiSCs to an ESC-like state
mESCs transition to an EpiSC-like state with LIF inhibition and FGF activation
Summary
Mouse epiblast stem cells (EpiSCs) are cultured with FGF2 and Activin A, like human embryonic stem cells (hESCs), but the action of the associated pathways in EpiSCs has not been well characterized. Here, we show that activation of the Activin pathway promotes self-renewal of EpiSCs via direct activation of Nanog, whereas inhibition of this pathway induces neuroectodermal differentiation, like in hESCs. In contrast, the different roles of FGF signaling appear to be only partially conserved in the mouse. Our data suggest that FGF2 fails to cooperate with SMAD2/3 signaling in actively promoting EpiSC self-renewal through Nanog, in contrast to its role in hESCs. Rather, FGF appears to stabilize the epiblast state by dual inhibition of differentiation to neuroectoderm and of media-induced reversion to a mouse embryonic stem cell-like state. Our data extend the current model of cell fate decisions concerning EpiSCs by clarifying the distinct roles played by FGF signaling.
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