Perspectives on Pedersen Lab Human-Mouse Chimera Paper

A new Cell Stem Cell paper by Victoria L. Mascetti and Roger Pedersen on human-mouse chimera modeling is quite interesting and important. I really enjoyed this short paper, but I do have a reservation about one way that it is being interpreted.

The authors show that human pluripotent stem cells (hPSC) including induced pluripotent stem cells and embryonic stem cells (hIPSC and hESC, respectively) are pluripotent in vivo during early development.

They come to four main conclusions as outlined in their highlights section:

• •hiPSCs and hESCs form human-mouse interspecies chimeras with high efficiency
• •hPSCs colonize gastrula-stage embryos in a manner predicted by fate mapping
• •Integrated human cells disperse widely and express relevant differentiation markers
• •Human-mouse chimeras provide in vivo functional validation of hPSC pluripotency

Very cool. Previous studies had not been able to so clearly define hESC and hIPSC pluripotency in these kinds of chimera assays.The studies have important implications for hPSC biology and function as well as embryogenesis.

In a Cambridge Press Release (PR) safety implications are invoked and that was picked up by others in the media:

“Our study provides strong evidence to suggest that human stem cells will develop in a normal – and importantly, safe – way. This could be the news that the field of regenerative medicine has been waiting for”

However, I’m not so convinced that these assays tell us a great deal about pluripotent stem cell safety in the regenerative medicine patient context.

While it is notable that the hPSC did not disrupt development via tumor formation such as production of teratoma, it’s not clear that this news bears so much on regenerative medicine safety. Part of the reason that the hPSC behaved normally here is almost certainly due to the early mouse embryo context into which they were placed. Transplantation of hPSC or more likely hPSC derivatives into an adult human patient for example would not have much relevance to these early mouse-human chimera development assays in the paper. Outside of the proper early embryo context, hPSC can and do sometimes form teratoma.

Overall the paper is intriguing and encouraging for the field. Another quote from the same PR hits the nail on the head:

Ms Mascetti adds: “Our finding that human stem cells integrate and develop normally in the mouse embryo will allow us to study aspects of human development during a window in time that would otherwise be inaccessible.”

This human-mouse chimera assay could be a brilliant tool for probing aspects of human development. Kudos to the authors.