Derivation of Functional Spermatogonia Stem Cells from Rhesus Macaque iPSCs

总结 目前，全世界约15%的夫妇和美国约12%的男性生育力低下或不育。一些 这种不育症的根本原因在于遗传缺陷，但其他原因是由于暴露于工业和环境 毒物、损伤或医学治疗，例如几乎总是导致不育的烷基化化疗， 尤其是在男人身上男性青春期前癌症患者的风险尤其高，因为他们无法提供一个 癌症治疗前的精液样本青春期前儿科癌症患者的生育能力保留 一个不断发展的新兴领域然而，治疗选择有限。自1980年以来，辅助生殖 技术（ART）已获得全世界的认可，卵胞浆内单精子注射（ICSI）自 帮助严重不孕的夫妇怀孕。然而，这些先进的技术需要 甚至产生少量的功能性配子。对于那些因非遗传因素而不育的个体， 根本原因无法产生配子，如儿童癌症幸存者，没有治愈他们的不育症。 随着包括睾丸癌和生殖细胞癌在内的儿科癌症发病率持续上升， 需要开发新的基于干细胞的疗法来治疗患者的男性因素不孕症， 通过药物治疗使不育。患者特异性多能干细胞代表了一个未来的潜在来源， 通过在体外产生生殖系前体，如精原干细胞（SSCs）， 在移植后恢复体内生育能力。这种治疗方法将使不育男性产生 与伴侣生下后代，而无需使用先进的生殖技术，如ICSI。我们的团队 率先将自体和供体恒河猴精原干细胞移植到受体恒河猴睾丸中， 寄生在睾丸中恢复生育能力此外，我们的研究小组是第一个从骨髓中获得SSC样细胞的研究小组。 人诱导多能干细胞（iPSC）。在这里，我们假设NHP iPSC衍生的SSC可以是 移植到绝育的自体受体睾丸中以恢复生育能力。此外，我们假设精子 从移植受体产生的胚胎和后代可以产生健康的胚胎和后代。根据PAR- 16-093基于干细胞的再生医学动物模型的改进（R 01）将使用 非人灵长类干细胞模型，iPSC是否可用于治疗男性因素不育症。

Summary Currently, ~15% of couples worldwide and ~12% of men in the United States are subfertile or infertile. Some root causes for this infertility lie in genetic defects, but others are due to exposure to industrial and environmental toxicants, injury, or medical treatments such as alkylating chemotherapies which almost always result in sterility, especially in men. Male pre-pubertal cancer patients are especially at risk since they are unable to provide a semen sample prior to their cancer treatments. Fertility preservation in pre-pubertal pediatric cancer patients is an emerging and ever-evolving field. However treatment options are limited. Since 1980, Assisted Reproductive Technology (ART) has gained worldwide acceptance and Intracytoplasmic Sperm Injection (ICSI) has since aided couples with severe infertility to achieve pregnancies. However, these advanced techniques require the production of even a small amount of functional gametes. For those individuals rendered sterile by non-genetic root causes unable to produce gametes, such as pediatric cancer survivors, there are no cures for their infertility. As the incidences of pediatric cancers, including testicular and germ cell cancers, continue to rise, there is a need for the development of novel stem-cell based therapies to treat male factor infertility in patients rendered sterile by medical treatments. Patient-specific pluripotent stem cells represent one future potential source to restore fertility by generating germline precursors such as spermatogonial stem cells (SSCs) in vitro that can restore fertility in vivo following transplantation. This therapeutic approach would allow infertile men to produce offspring with their partners without having to use advanced reproductive technologies such as ICSI. Our team has pioneered the ability to transplant autologous and donor rhesus SSCs into recipient rhesus testes to re- colonize the testis and restore fertility. Additionally, our group was the first group to derive SSC-like cells from human induced pluripotent stem cells (iPSCs). Here, we hypothesize that NHP iPSC-derived SSCs can be transplanted into sterilized autologous recipient testes to restore fertility. Furthermore, we hypothesize that sperm generated from transplanted recipients can produce healthy embryos and offspring. This proposal under PAR- 16-093 Improvement of Animal Models for Stem Cell-based Regenerative Medicine (R01) will determine, using a non-human primate stem cell model, whether iPSCs can be utilized to treat male factor infertility.