Accelerated Maturation of Primate Testis by Xenografting into Mice1

Abstract

Testicular maturation and sperm production throughout the life of the male form the basis of male fertility. It is difficult to elucidate the intricate processes controlling testicular maturation and spermatogenesis in primates in vivo due to the long time span required for sexual maturation and also to the lack of accessible in vitro or in vivo models of primate spermatogenesis. Ectopic xenografting of neonatal testis tissue into mice provides an accessible model to study and manipulate the propagation and differentiation of male germ cells from immature donor animals. However, it was not clear whether this approach would be applicable to slowly maturing primates. Here we report that grafting of testis tissue from immature rhesus monkeys (Macaca mulatta) into host mice resulted in the acceleration of testicular maturation and production of fertilization-competent sperm in testis xenografts. The system reported here provides a powerful, practical approach to study timing and control of testicular maturation and regulation of primate spermatogenesis without the necessity for experimentation in primates. This approach could potentially be applied to produce fertile sperm from sexually immature individuals of rare or valuable primate species or from prepubertal boys undergoing sterilizing therapy for cancer.

Generation of macaques with sperm derived from juvenile monkey testicular xenografts

“…Furthermore, we found that the 14-month-old WT monkey-derived testis xenografts collected 12 months after the implantation (with an equivalent age of 14 + 12 = 26 months; Figure 1F) showed large-diameter seminiferous tubules and mature sperm, whereas natural testicular tissues obtained from the 27-month-old TG monkey before xenografting showed seminiferous tubules of small diameters, indicating their relatively immature differentiation ( Figure 1G and Supplementary information, Figure S1). This finding was consistent with a previous study by Honaramooz et al [3], in which comparison was made between the seminiferous tubules in the xenografts and those in natural monkeys of similar ages. Taken together, these data suggest that testicular tissue development is accelerated in the xenografts.…”

“…The testis tissue from young mammals, including mice and monkeys, is capable of undergoing complete spermatogenesis in xenografts, and sperms obtained from monkey testicular tissue xenografts have yielded monkey blastocysts after intracytoplasmic sperm injection (ICSI), although no successful production of primates has been reported [2][3][4]. Achieving the latter is important because of its potential implication for restoring fertility of young cancer patients undergoing radiotherapy and chemotherapy.…”

Ectopic porcine spermatogenesis in murine subcutis: tissue grafting versus cell-injection methods

“…For instance, it can advance the initiation of spermatogenesis in primates, which otherwise have long pre-pubertal periods. The grafted primate testis tissue fragments showed accelerated maturation, and fertilization-competent sperms were produced upon xenograft in host mice [15]. In addition, the use of small experimental animals should facilitate any experimental manipulations like local or systemic administration of hormones or factors to the recipients.…”

Can we grow sperm? A translational perspective on the current animal and human spermatogenesis models

“…Successful xenografts of fresh and cryopreserved testicular tissue have been reported in a variety of species, including: mouse, 26,27 hamster, 28 rabbit, 29 pig, 30 goat, 26 sheep, 26,31 cattle, 32,33 cat, 34 horse 35 and nonhuman primates. 36 Although the risk of retroviral genetic contamination does exist using this xenograft model, consistent graft recovery and complete spermatogenesis have made this model a valuable tool for animal reproductive and toxicology studies.…”

“…37 This finding seen with human testis xenografts is similarly seen in animal studies where xenografts made from immature testis tissue had better survival and accelerated maturation once transplanted. 36 For still unknown reasons, mature testis tissue grafts do not support germ cell differentiation as well as immature testis tissue grafts in xenograft models. 38 To further demonstrate this finding, Yu and colleagues 39 transplanted fetal (20-26 weeks) human testicular tissue subcutaneously onto an immunodeficient nude mouse and demonstrated that the xenograft could survive for more than 135 days.…”