Scientists at Salk Institute have made breakthroughs in the integration of human cells into embryos of a different species

Scientists at Salk Institute for Biological Studies in California have made breakthroughs on multiple fronts in the race to integrate pluripotent stem cells from one species into the early-stage development of another. This will allow to study the embryonic development of an organism, diseases, test new therapeutic drugs and the possibly grow transplantable. Dr. Juan Carlos Izpisúa, professor in Salk’s Gene Expression Laboratory, leads this study published in today’s issue of the journal Cell. Dr. Josep M. Campistol, CEO and nephrologist in Hospital Clínic and researcher in IDIBAPS, and scientists from the Catholic University of Murcia (UCAM), the Pedro Guillén Foundation, the CEMTRO Clinic in Madrid and the University of Murcia, have also participated.

Rapid advances in the ability to grow cells, tissues and organs of one species within an organism of a different species offer an unprecedented opportunity for tackling longstanding scientific mysteries and addressing pressing human health problems, particularly the need for transplantable organs and tissues.

In the article published in the journal Cell scientist have combined CRISPR/Cas9 and pluripotent cells technologies, to grow a rat pancreas, heart and eyes, in a developing mouse, and have shown that functional organs of a species can be grown in another. For the first time, these experts have also been able to generate human cells and tissues in early stage pig and cattle embryos, marking the first step toward the generation of transplantable human organs using large animals whose organ size, physiology and anatomy are similar to humans. On the other hand, the team of researchers has shown that the integration of cells of divergent species might prove more difficult than combining cells form rats and mice, which are closer evolutionary species.

“Our findings may offer hope for advancing science and medicine by providing an unprecedented ability to study early embryo development and organ formation, as well as a potential new avenue for medical therapies,” says Salk Professor Juan Carlos Izpisua Belmonte, a senior author of the paper and a leading expert in this field. “We have shown that a precisely targeted technology can allow an organism from one species to produce a specific organ composed of cells from another species. This provides us with an important tool for studying species evolution, biology and disease, and may lead ultimately to the ability to grow human organs for transplant.”

An interspecies chimera is an organism containing cells from different species. The word “chimera” originally described mythological creatures or deities in polytheistic religions. In science, interspecies chimeras have emerged as valuable basic research tools with potential for future clinical applications

In one experiment, they used the gene-editing technology known as CRISPR-Cas9 on mouse embryos to turn off the gene that makes the pancreas. They then inserted rat pluripotent stem cells, which contained an intact pancreas gene, into each mouse embryo. Once implanted in surrogate mouse mothers, the embryos developed normally—except for the fact that each mouse was growing a rat pancreas. This success led the team to try growing other rat organs in mice, including eyes and heart.

Surprisingly, they also observed that rat pluripotent stem cells generated a gallbladder in a mouse, an organ that is not present in rats. “Our rodent experiments reveal a profound secret, that a developing mouse was able to unlock a gallbladder developmental program in rat cells that is normally suppressed during rat development,” said Jun Wu, a Salk staff scientist and lead author of this paper. “This highlights the importance of the host environment in controlling organ development and evolutionary speciation.” Wu said the experiment with mice and rats also showed that growing human organs for transplant in animals might actually be possible. “Each mouse was healthy and had a normal lifespan, which indicated that the development proceeded properly.”

It is not practical to grow human organs in mice or rats, however, because rodents are simply too small and developmentally different. So in other experiments, the team turned to pigs, whose organ sizes and developmental timescales are more comparable to ours. After generating several different types of human induced pluripotent stem (iPS) cells, the scientists inserted the most promising types into pig embryos and successfully implanted sows with those embryos. The researchers stopped the experiment at four weeks in order to evaluate the technology’s safety and effectiveness to that point.

Some embryos showed that the human cells within were beginning to specialize and turn into tissue precursors, though the success rate and level of human iPS cell contributions in pigs were much lower than for mouse embryos containing rat cells.

Although the results represent the first successful attempt of integrationg human iPS cells into a large animal species, the scientists underscore that research is in very early stages and significant challenges remain to developing medical therapies based on the technology. Dr. Josep M. Campistol points out that “the aim of this multidisciplinary study is to meet the needs of current medicine and constitutes the first stone for the introduction, in the future, of new methodologies for the transplantation of solid organs.”

“Of course, the ultimate goal of chimeric research is to learn whether we can use stem-cell and gene-editing technologies to generate genetically-matched human tissues and organs, and we are very optimistic that continued work will lead to eventual success,” says Izpisua Belmonte. “But in the process we are gaining a better understanding of species evolution as well as human embryogenesis and disease that is difficult to get in other ways.”

Future work will involve continuing to understand the limits to getting human cells to incorporate successfully into animals.

Source: Salk Institute