Basic research on uterus transplantation in nonhuman primates in Japan

Abstract

Uterus transplantation (UTx) is now a potential option for women with uterine factor infertility to have a child. However, UTx is still in an experimental stage and basic animal studies including in nonhuman primates are needed for accumulation of data that will provide important information for establishment of UTx in humans. Herein, we summarized our experiences using cynomolgus macaques, with the goal of promoting further development of UTx studies in nonhuman primates. Our basic studies using cynomolgus macaques were summarized, including the results of other teams in nonhuman primates. Our team in Japan launched UTx research in 2009 using cynomolgus macaques and has accumulated a large archive of results in the UTx research field, including examination of uterine blood flow, surgical procedures of autologous and allogeneic UTx, organ perfusion methods in deceased donor models, immunological response and rejection and ischemia/reperfusion injury. We achieved the first delivery after autologous UTx in primates and the first periodic recovery of menstruation after allogeneic UTx in nonhuman primate models. Results from animal studies, including those in nonhuman primates, provide the basis for clinical application of UTx. Therefore, our accumulated data since 2009 and our basic experience in cynomolgus macaque are meaningful for future UTx trials in Japan. In addition, more validation in nonhuman primate models is needed for resolution of medical issues and further development of UTx in humans, despite clinical application of UTx in several countries.

Experimental techniques for the development of a uterus transplantation model in cynomolgus macaques

“…After accumulating a large amount of data after experiments on cynomolgus macaques for more than a decade, we have already established the surgical skills and techniques involved in UTx. 8 We are now aiming for the clinical application of UTx in humans in Japan. Furthermore, we have worked with the Japan Society of Obstetrics and Gynecology and the Japanese Society for Transplantation with regard to execution of this clinical application in Japan.…”

“…7 We have accumulated many data on UTx research including examination of uterine blood flow, surgical procedures for autologous and allogeneic UTx, method for organ perfusion in a deceased donor model, immunological response and rejection, and ischemia/reperfusion injury over more than a decade. 8 We have also overcome many difficulties which arose from specific differences between humans and animal models even though nonhuman primates have similarities with humans. Consequently, we have succeeded in our first delivery after an autologous UTx in a primate, 9 and after allogeneic UTx in non-human primates (unpublished data).…”

Clinical pregnancy after deceased donor uterus transplantation: Lessons learned and future perspectives

“…The following three stages that assess the outcome/success of UTx require consideration: (i) an early favorable surgical UTx outcome with a viable graft by 3 months, (ii) graft function by 1 year with several months of regular menstruation, and (iii) a successful pregnancy with the delivery of a healthy baby . After successful animal‐based research the first human living donor (LD) UTx was attempted in 2000 in Saudi Arabia followed by a single‐case of UTx involving a deceased donor (DD) in Turkey 11 years later, which had both surgical and functional success; moreover, other cases of clinical pregnancies with repeated early‐stage miscarriages were reported . Nevertheless, this case provided proof of concept that pregnancy can occur in a transplanted human uterus.…”

Concerns Associated with Uterus Transplantation in Japan

“…We have performed basic experiments in cynomolgus monkeys for more than a decade and gathered extensive data. 6 Consequently, our approach has been deemed suitable for UTx in humans by academics and specialists in obstetrics and gynecology, transplant surgery, and ethics. However, conservative opinion in Japan poses an obstacle to the clinical application of UTx.…”