Interspecies chimerism is a phenomenon of an organism consisting of tissue and genetic information from two different species. Currently, many studies investigate the use of interspecies chimerism with human pluripotent stem cells (hPSCs) to generate functional human cells, tissues or organs in large animals, which is expected to solve the shortage of functional tissues and organs for transplant. However, hPSCs interspecies chimerism faces barriers due to the extremely low chimeric contribution of hPSCs.