DALLAS – Dec. 0, 2025 Failure of human pluripotent stem cells (PSCs) to survive when grown with the PSCs of distantly related species occurs because of an innate immune reaction in the nonhuman cells, a study led by UT Southwestern Medical Center researchers suggests. The findings, published in Cell1, could help researchers remove a key barrier to growing human organs in other species for transplant.
“Our ultimate goal is to use human PSCs to generate organs and tissues in animals to overcome the worldwide shortage of organ and tissue donors. This research uncovers a previously unrecognized role for RNA innate immunity in cell competition and interspecies chimerism that’s blocking us from reaching that objective.”
Jun Wu, Ph.D., Associate Professor of Molecular Biology at UT Southwestern and a New York Stem Cell Foundation (NYSCF)-Robertson Investigator.
Associate Professor of Molecular Biology at UT Southwestern and a New York Stem Cell Foundation (NYSCF)-Robertson Investigator.
Dr. Wu co-led the study with Yingying Hu, Ph.D., former Assistant Instructor in the Wu Lab, and Masahiro Sakurai, Ph.D., Research Scientist in the Wu Lab. Dr. Hu is currently a Senior Research Associate in the lab of Elizabeth Chen, Ph.D., Professor of Molecular Biology.
The Wu Lab is particularly interested in learning how to grow human cells with those of other species research that could eventually lead to generating full human organs in animals and that sheds light on developmental processes in humans and other species. In 20212, Dr. Wu and his colleagues showed that when human PSCs were grown in lab dishes with the PSCs of distantly related species such as mice or rats, the human cells gradually died off while the other species’ cells thrived.
Why human PSCs were the “losers” in this co-culture competition was not fully understood, Dr. Wu explained. Although subsequent research showed it’s possible to help the human cells survive by genetically altering a molecular pathway responsible for programmed cell death, this tweak could cause problems in tissues and organs destined for transplant, he added. Thus, finding ways to mitigate this competitive process in the other species’ cells and embryos would be preferable.
Toward this end, Dr. Wu and his colleagues searched for any role the nonhuman cells might play in harming the human cells by growing mouse and human PSCs together in lab dishes and comparing the mouse cells’ gene expression activity with that of mouse cells grown without human cells. Their work revealed that a molecular cascade known as the retinoic acid-inducible gene I-like receptor (RLR) pathway was significantly more active in the co-cultured mouse cells compared with the mouse cells growing alone. This pathway is responsible for sensing foreign RNAs in cells a consequence of some viral infections and turning on immune activity to fight these invaders.
To determine if the RLR pathway was responsible for killing the co-cultured human cells, it was shut down in the mouse cells by turning off a key gene in the cascade responsible for producing the mitochondrial antiviral signaling protein, or MAVS, discovered at UTSW by Zhijian “James” Chen, Ph.D., Professor of Molecular Biology and in the Center for the Genetics of Host Defense. Significantly more human cells survived after this alteration, suggesting RNA innate immunity in the mouse cells was responsible for harming the human cells.
Further study revealed small amounts of human RNA in the co-cultured mouse cells and vice versa, suggesting the cells had exchanged RNA molecules. A closer look through microscopy suggested this exchange happened through tunneling nanotubes (TNTs), bridges formed by extensions of the cell membrane. When the researchers shut down TNT formation, more human cells survived. Notably, when human cells were injected into mouse embryos lacking MAVS, significantly more survived than those in mouse embryos with MAVS.
Dr. Wu said these findings offer multiple targets that scientists can use to increase the survival of human PSCs growing with PSCs or within embryos of other species a step that brings growing human organs in animals closer to fruition.
Dr. Wu is a Virginia Murchison Linthicum Scholar in Medical Research. He is a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences, the Harold C. Simmons Comprehensive Cancer Center, and the Hamon Center for Regenerative Science and Medicine at UTSW. Dr. James Chen holds the George L. MacGregor Distinguished Chair in Biomedical Science.
References:
1) https://www.cell.com/cell/abstract/S0092-8674(25)01244-9
2) https://www.nature.com/articles/s41586-021-03273-0
3) https://www.utsouthwestern.edu/departments/genetics-host-defense/
(Newswise/HG)
