Interspecies chimeras – will farm animals be regenerative medicine vehicles of the future?



Hiromitsu Nakauchi has a vision for regenerative medicine. In this vision, he sees a renewable source of human organs for transplantation that are grown within the bodies of farm animals.

Here’s how it works: pluripotent stem cells would be injected into an early animal embryo that is not capable of generating a specific organ. As the animal embryo develops, the human pluripotent cells would differentiate into the missing organ. This human organ would then be removed and transplanted into a patient.

To me this sounds like an idea right out of a sci-fi movie. But is this a realistic goal to work towards? Nakauchi seems to think so, but many others aren’t so sure.

Two major questions that would need to be addressed are:

1) Can normal pluripotent stem cells create an entire organ in another animal?

2) Can pluripotent stem cells from one animal generate an entire organ in another animal species?

In 2010, Nakauchi published a report in Cell describing the generation of a rat pancreas in a mouse, a finding that provides the answer “yes” to both of the above questions. Normal rat pluripotent stem cells were injected into a mouse embryo in which a key gene involved in pancreas development had been deleted (leaving the mouse incapable of forming a pancreas) and indeed rat pluripotent stem cells were able to generate a functioning rat pancreas in the mouse.

This month in the American Journal of Pathology, Nakauchi’s group published the generation of kidney from induced pluripotent stem cells in a mouse lacking a key kidney developmental gene using the same technology.

At the ISSCR meeting earlier this month in Yokohama, Japan, Nakauchi described his work translating this technology to large farm animals. Using two transgenic pig lines, normal, fluorescent orange pig pluripotent stem cells were injected into a pancreas incompetent pig embryo. The result: a chimeric pig with a fluorescent orange pancreas.

In Japan (and many other countries), pluripotent stem cells cannot legally be injected into another embryo for the generation of chimeras, thus the long-term goal of generating interspecies chimeras between human and pig could not be tested. Nakauchi told the audience that he would need collaborators from other countries to perform these experiments.

In the audience, there was excitement surrounding the idea of growing human organs for transplantation in farm animals however, many concerns were raised. One audience member asked what would be done to prevent human-pig chimerism in the brain if these experiments were to be translated to these species. Indeed, chimerism was observed in almost all organs in rat-mouse chimeras.

To prevent interspecies brain chimerism, Nakauchi suggested deleting a gene essential for brain development in human pluripotent stem cells, which would prevent them from forming any brain tissue. In discussions following the talk, it was suggested that human pluripotent stem cells could be engineered to restrict their potential to only the organ of interest such as pancreas. However, this creates another set of concerns surrounding the use of genetically engineered cells for regenerative medicine in human patients.

Some think this technology is a stretch and question whether human cells would be capable of integrating into a pig blastocyst and creating a human organ in this environment, as rat cells were able to in mouse. Non-human primate-pig chimeras would provide additional support for this idea.

Will farm animals be viable vehicles for human organ generation? I guess we will have to wait and see.