Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Andrology. 2021 Sep;9(5):1603-1616. doi: 10.1111/andr.13033. Epub 2021 Jul 7.
Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but no studies have involved cytotoxic treatment before puberty and transplantation after puberty, which would be the most likely clinical scenario.
To evaluate donor-derived functional sperm production after SSC transplantation to adult monkeys that had received testicular irradiation during the prepubertal period.
We obtained prepubertal testis tissue by unilaterally castrating six prepubertal monkeys and 2 weeks later irradiated the remaining testes with 6.9 Gy. However, because spermatogenic recovery was observed, we irradiated them again 14 months later with 7 Gy. Three of the monkeys were treated with GnRH-antagonist (GnRH-ant) for 8 weeks. The cryopreserved testis cells from the castrated testes were then allogeneically transplanted into the intact testes of all monkeys. Tissues were harvested 10 months later for analyses.
In three of the six monkeys, 61%, 38%, and 11% of the epididymal sperm DNA were of the donor genotype. The ability to recover donor-derived sperm production was not enhanced by the GnRH-ant pretreatment. However, the extent of filling seminiferous tubules during the transplantation procedure was correlated with the eventual production of donor spermatozoa. The donor epididymal spermatozoa from the recipient with 61% donor contribution were capable of fertilizing rhesus eggs and forming embryos. Although the transplantation was done into the rete testis, two GnRH-ant-treated monkeys, which did not produce donor-derived epididymal spermatozoa, displayed irregular tubular cords in the interstitium containing testicular spermatozoa derived from the transplanted donor cells.
The results further support that sperm production can be restored in non-human primates from tissues cryopreserved prior to prepubertal and post-pubertal gonadotoxic treatment by transplantation of these testicular cells after puberty into seminiferous tubules.
由于精原干细胞（SSC）的废除，青春期前患者的癌症治疗会影响未来的生育能力。在猕猴中，通过将 SSCs 进行睾丸内移植可以再生精子发生，但尚无研究涉及青春期前接受细胞毒性治疗和青春期后进行移植的情况，这将是最有可能的临床情况。
评估在青春期前接受睾丸照射的成年猕猴中，SSC 移植后供体来源的功能性精子产生情况。
我们通过单侧去势 6 只青春期前的猕猴获得了青春期前的睾丸组织，两周后用 6.9Gy 照射剩余的睾丸。然而，由于观察到精子发生恢复，我们在 14 个月后用 7Gy 再次照射。其中 3 只猕猴接受了 GnRH 拮抗剂（GnRH-ant）治疗 8 周。然后将冷冻的去势睾丸细胞同种异体移植到所有猕猴的完整睾丸中。10 个月后收获组织进行分析。
在 6 只猕猴中的 3 只中，61%、38%和 11%的附睾精子 DNA 来自供体基因型。GnRH-ant 预处理并不能增强恢复供体源性精子产生的能力。然而，移植过程中曲细精管的填充程度与最终产生供体精子有关。来自供体贡献 61%的受者附睾精子能够使恒河猴卵子受精并形成胚胎。尽管移植是在 rete testis 中进行的，但在 2 只接受 GnRH-ant 治疗的猕猴中，由于没有产生供体衍生的附睾精子，在含有源自移植供体细胞的睾丸精子的间质中显示出不规则的管状索。
这些结果进一步支持，通过在青春期前和青春期后性腺毒性治疗前冷冻保存组织，并在青春期后将这些睾丸细胞移植到曲细精管中，可以在非人类灵长类动物中恢复精子发生。
