Mouse models aren’t good enough for human stem cell research


Mice are a common model system for clinical research. This also applies to embryonic stem cells, since mouse embryonic stem cells (mESCs) grow and differentiate like human embryonic stem cells (hESCs). However, further work has shown that there are many molecular differences between mESCs and hESCs. This is the case even though complete sequences of mouse and human genomes have revealed that 99% of mouse genes encode for corresponding genes in humans. Now a paper from the Max Planck Institute indicates that mouse models may not be very good representatives of the developmental behaviors of hESCs.

This researcher group, led by Hans Schöler, found that mouse epiblast cells, which were believed to be the closest animal-based model to hESCs, behave differently in the presence of the growth factor FGF than their human counterparts. “Our latest study demonstrates that animal model systems are inadequate for a great many tests,” Schöler said in a press release.

There has been a fair amount of curiosity among stem cell scientists to determine how accurately findings from mESCs parallel hESCs. hESCs and mESCs share several characteristics: they are both pluripotent, and have an active Oct4 gene that serves as a transcription factor.

However, hESCs and mESCs have some distinct differences. Signaling pathways used to differentiate mESCs into liver, nerve, or muscles cells produce either no effect or completely different effects in hESCs.

In 2007, scientists seeking a better animal model for human tissues discovered a new type of pluripotent cell in mice.  They called this cell “mouse epiblast stem cells,” or “EpiSCs.”  EpiSCs are pluripotent, but they are unlike mESCs in that they are not made from early pre-implantation embryos, but from a later stage of embryonic development, when the embryo has already implanted into the uterus.  Although EpiSCs are more advanced in their development than a typical mESC, they share some important similarities with hESCs than mESCs.  For example, both EpiSCs and hESCs can be grown and preserved in their pluripotent state with the addition of the growth hormones FGF2 and Activin A.  “EpiSCs from mice are therefore more-or-less equated with hESCs in the general scientific discussion,” said lead author Boris Greber.

To determine how accurately EpiSCs mimicked hESCs, Greber and his collaborator Schöler and their co-workers evaluated how these two cell types behaved in the presence of different growth factors and inhibitors.  Two growth factors called “Activin” and “FGF” are both active in EpiSCs and hESCs.  Activin promotes self-renewal in both EpiSCs and hESCs by communicating with a signal transduction pathway that uses SMAD2/3 and a protein called Nanog.

FGF, however, was another story.  Even though Activin works similarly in both cell types, FGF works with Activin to signal SMAD2/3 and Nanog to promote self-renewal in hESCs.  However, in EpiSCs FGF does not signal SMAD2/3 and Nanog, but signals the gene Klf2, which activates pluripotency. Klf2 expression in EpiSCs keeps the cells in their pluripotent state, and inhibits differentiation into neural-like tissue, and prevent EpiSCs from reverting to an earlier stage of embryonic development.  Because FGF growth hormone has different effects in EpiSCs and hESCs, EpiSC differentiation probably does not accurately represent the differentiation process in hESCs.

This paper argues for the centrality of hESCs in future stem cell studies.  Reprogramming technologies and mechanisms for differentiating stem cells still have a long way to go before they are fully understood, since there are probably molecular differences between induced pluripotent stem cells and hESCs that are not apparent from simply looking at them.  “We will still need hESCs as the gold standard against which to compare everything else,” said Schöler.

Schöler also said that testing in somatic human cells would not replace tests in embryonic cells because there is still very little understanding about the signaling pathways that control the differences between the two cell types. “The recent successes in reprogramming mature human somatic cells make it look as though tests using hESCs are nowadays redundant,” said Schöler. “But appearances are deceptive.”