Rescue of Fertility in Homozygous Mice for the Urokinase Plasminogen Activator Transgene by the Transplantation of Mouse Hepatocytes

Development of the urokinase plasminogen activator/SCID (uPA/SCID) transgenic mouse model has opened new perspectives for the study of different biological mechanisms Such as liver regeneration, stern cell differentiation, and human hepatic pathogens. We observed that homozygous uPA/SCID mice (uPA(+/+)/SCID) had a small offspring, indicating a fertility defect. The goal of this study was thus to rescue the fertility of homozygous uPA mice. A deregulation of ovarian function with an absence of corpus luteum was observed in female uPA(+/+)/SCID mice. In male uPA(+/+)/SCID mice, a decrease of the weight of (lie testes, epididymis, seminal vesicle, and prostate was measured. This was associated with,in absence of seminal and prostatic secretions and a reduction in testicular sperm production. We hypothesized that the infertility of mice was the consequence Of uPA-induced liver injury. Thus, in order to rescue liver function, hepatocytes from mice negative for the uPA transgene were transplanted into uPA(+/+)/SCID mice. Thirty days after cell transplantation. the livers of transplanted uPA(+/+)/SCID mice were totally repopulated and presented a normal morpholooy. Furthermore, transplantation restored normal body weight, life span, and reproductive organ function. In conclusion. we demonstrated that the transplantation of uPA(+/+)/SCID mice with healthy hepatocytes was Sufficient to rescue the reproductive capacity of female and male uPA homozygous annuals, highlighting the importance of normal liver function to reproductive capability.