Derivation of Functional Spermatogonia Stem Cells from Rhesus Macaque iPSCs

从恒河猴 iPSC 中衍生出功能性精原干细胞

• 批准号: 10187673
• 负责人: Charles A. Easley
• 金额: $ 71.24万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187673
• 关键词: Address; Adult; Animal Model; Animals; Assisted Reproductive Technology; Autologous; Autologous Transplantation; Cancer Patient; Cells; Child; Childhood; Clinic; Clinical; Couples; Derivation procedure; Development; Disease; Embryo; Exposure to; Fertility; Fetal Development; Future; Gametogenesis; Genetic; Germ Cells; Haploidy; Health; Human; Immune; Implant; In Vitro; Incidence; Individual; Industrialization; Infertility; Injury; Intervention; Intracytoplasmic Sperm Injections; Left; Macaca mulatta; Male Infertility; Malignant Childhood Neoplasm; Medical; Modeling; Molecular Profiling; Mutation; Oocytes; Patients; Plant Roots; Pluripotent Stem Cells; Pregnancy; Production; Protocols documentation; Regenerative Medicine; Reproductive Technology; Research; Rhesus; Risk; Sampling; Seminal fluid; Skin; Source; Spermatids; Spermatocytes; Spermatogenesis; Spermatogenic Cell; Spermatogonia; Stem cell transplant; Sterility; Sterilization; Techniques; Testicular malignant germ cell tumor; Testing; Testis; Therapeutic; Toxic Environmental Substances; Translating; Transplant Recipients; Transplantation; United States; Work; blastocyst; cancer therapy; chemotherapy; childhood cancer survivor; clinical translation; embryonic stem cell; fertility preservation; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; male; male fertility; men; non-genetic; nonhuman primate; novel; offspring; prepuberty; sperm cell; stem cell differentiation; stem cell model; stem cell therapy; stem cells; stem-like cell; success; toxicant

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.

概括 目前，全球约 15% 的夫妇和美国约 12% 的男性生育能力低下或不育。一些 不孕不育的根本原因在于遗传缺陷，但其他原因则是由于接触工业和环境造成的。 毒物、伤害或药物治疗，例如烷基化化疗，几乎总是导致不育， 尤其是男性。男性青春期前癌症患者尤其面临风险，因为他们无法提供治疗 在癌症治疗之前采集精液。青春期前儿童癌症患者的生育能力保留 一个新兴且不断发展的领域。然而，治疗选择有限。自1980年起，辅助生殖 技术 (ART) 已获得全世界的认可，胞浆内单精子注射 (ICSI) 自此 帮助严重不孕不育的夫妇实现怀孕。然而，这些先进技术需要 即使是少量的功能性配子的产生。对于那些因非遗传因素导致不育的个体 无法产生配子的根本原因，例如儿科癌症幸存者，他们的不孕症无法治愈。 随着儿童癌症（包括睾丸癌和生殖细胞癌）的发病率持续上升， 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育症 通过医学治疗进行无菌治疗。患者特异性多能干细胞代表了未来的一种潜在来源 通过在体外产生精原干细胞（SSC）等种系前体来恢复生育能力 移植后恢复体内生育能力。这种治疗方法将使不育男性能够生育 无需使用 ICSI 等先进生殖技术即可与伴侣生育后代。我们的团队 率先将自体和供体恒河猴 SSC 移植到受体恒河猴睾丸中，以重新 定植睾丸并恢复生育能力。此外，我们的团队是第一个从 SSC 中衍生出 SSC 样细胞的团队。 人类诱导多能干细胞（iPSC）。在这里，我们假设 NHP iPSC 衍生的 SSC 可以 移植到绝育的自体受者睾丸中以恢复生育能力。此外，我们假设精子 移植受者产生的胚胎可以产生健康的胚胎和后代。该提案根据 PAR- 16-093 基于干细胞的再生医学动物模型的改进（R01）将确定，使用 非人灵长类干细胞模型，iPSC是否可以用于治疗男性因素不育症。