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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. Owing 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.

Extensive contribution of embryonic stem cells to the development of an evolutionarily divergent host