Human Molecular Genetics Advance Access published online on October 3, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm282
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Extensive contribution of embryonic stem cells to the development of an evolutionarily divergent host
,*,21 Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou 510080, China. 2 Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. 3 Department of Veterinary Clinical Sciences, University of Liverpool, Liverpool, UK.
* To whom correspondence should be addressed. Tel: +86 2087335822; Fax: +86 2087335858; Email: xiangp{at}mail.sysu.edu.cn; Tel: +1 7738344393; Fax: +1 7737020271; Email: blahn{at}bsd.uchicago.edu
Received August 21, 2007; Revised September 17, 2007; Accepted September 21, 2007
The full potential of embryonic stem (ES) cells to generate precise cell lineages and complex tissues can be best realized when they are differentiated in vivo - i.e., in developing blastocysts. Due to various practical and ethical constraints, however, it is impossible to introduce ES cells of certain species into blastocysts of the same species. One solution is to introduce ES cells into blastocysts of a different species. However, it is not known whether ES cells can contribute extensively to chimerism when placed into blastocysts of a distantly related species. Here, we address this question using two divergent species, Apodemus sylvaticus and Mus musculus, whose genome sequence differs by 
18% from each other. Despite this considerable evolutionary distance, injection of Apodemus ES cells into Mus blastocysts led to viable chimeras bearing extensive Apodemus contributions to all major organs, including the germline, with Apodemus contribution reaching 40% in some tissues. Immunostaining showed that Apodemus ES cells have differentiated into a wide range of cell types in the chimeras. Our results thus provide a proof of principle for the feasibility of differentiating ES cells into a wide range of cell types and perhaps even complex tissues by allowing them to develop in vivo in an evolutionarily divergent host - a strategy that may have important applications in research and therapy. Furthermore, our study demonstrates that mammalian evolution can proceed at two starkly contrasting levels: significant divergence in genome and proteome sequence, yet striking conservation in developmental programs.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.