Organizing and Reorganizing Human Testis Development In Vitro

体外组织和重组人类睾丸发育

• 批准号: 10817412
• 负责人: Monica M Laronda
• 金额: $ 57.87万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817412
• 关键词: 3-Dimensional; 3D Print; Adult; Age; Air; Animals; Architecture; Assisted Reproductive Technology; Autologous; Autologous Transplantation; Benchmarking; Blood-Testis Barrier; Bone Marrow Transplantation; Cell Fraction; Cell Maturation; Cells; Chemotherapy and/or radiation; Chicago; Clinic; Cryopreservation; Cryopreserved Tissue; Development; Embryo; Endothelial Cells; Engineering; Excision; Extracellular Matrix; Family suidae; Fertility; Fertilization; Freezing; Future; Genetic Transcription; Germ Cells; Goals; Gonadotropins; Grant; Human; Hydrogels; In Vitro; Individual; Infertility; Institution; Life; Liquid substance; Malignant neoplasm of testis; Medical; Microfluidic Microchips; Microfluidics; Morphology; Mus; Neonatal; Newborn Infant; Organ Culture Techniques; Organoids; Ovarian Tissue; Patients; Pediatric Hospitals; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Pregnancy; Printing; Production; Proteomics; Puberty; Publishing; Reproducibility; Reproduction; Reproductive Technology; Research; Resources; Rodent Model; Seminiferous tubule structure; Somatic Cell; Spermatogenesis; Stem cell transplant; Structure; Support System; System; Technology; Testicular Tissue; Testing; Testis; Testosterone; Tissue Grafts; Tissue Survival; Tissues; Translating; Transplantation; Tubular formation; bioink; boys; cancer cell; cancer therapy; cell age; clinical application; drug development; egg; experience; gender affirming therapy; gender dysphoria; girls; human model; in vivo; insight; leukemia; leydig interstitial cell; male; next generation; novel; novel strategies; oocyte cryopreservation; prepuberty; prevent; reconstruction; reproductive; restoration; safe patient; scaffold; screening; sertoli cell; sperm cell; stem cells; transgender

ABSTRACT This is a multi-PI, multi-institutional grant to develop physiomimetic systems that mimic human testis development and spermatogenic lineage development, ex vivo. Chemotherapy and radiation treatments for cancer or gender affirming treatments for transgender patients can cause infertility. Adult patients have the option to cryopreserve eggs or sperm prior to treatment that can be thawed in the future and used to achieve pregnancy with standard assisted reproductive technologies, including IVF. Those options are not available to all adult patients or to prepubertal patients who are not able to produce mature eggs or sperm. Although prepubertal boys or transgender girls who are on gender affirming treatments are not producing sperm, they do have spermatogonial stem cells SSCs in their testes that have the potential to produce sperm. The MPIs in Chicago and Pittsburgh have been cryopreserving immature testicular tissues for young patients for more than a decade with anticipation that those tissues can be thawed in the future and matured to produce sperm. Each patient donates a portion of their tissue to research to develop next generation technologies that will allow them to use their tissues for reproduction. We will use those tissues to gain fundamental insights into human testis development from newborn to adult stages of life. This will establish benchmarks to evaluate our progress engineering three novel testis physiomimetic systems that support spermatogenesis, ex vivo. Aim 1 will replicate mouse testicular tissue organotypic culture at the air/liquid interface using a microfluidics device and a static PDMS roof-transwell system before translating the approach to human testis tissues. Aim 2 will establish mouse and human testicular organoids, which will then be induced to fuse into elongated seminiferous tubule-like structures. Aim 3 will print seminiferous tubule like scaffolds using human testis extracellular matrix (htECM) and pig testis ECM (ptECM) hydrogels as bioink and then seed the scaffolds with mouse and human testicular somatic cells and germ cells. These testicular physiomimetic systems will provide fundamental insights into human testicular somatic cell and germ cell development and establish experimental platforms to test toxicologic or pharmaceutical compounds or drugs that promote or prevent sperm production. The overarching objective is to mature human testicular tissues in one or more of these physiomimetic systems to produce fertilization competent sperm, ex vivo.

抽象的 这是一项多 PI、多机构资助，用于开发模仿人类睾丸的拟态系统 离体发育和生精谱系发育。化疗和放射治疗 癌症或跨性别患者的性别肯定治疗可能会导致不孕。成年患者有 选择在治疗前冷冻保存卵子或精子，以便将来解冻并用于实现 通过标准辅助生殖技术（包括体外受精）怀孕。这些选项不适用于 所有成年患者或无法产生成熟卵子或精子的青春期前患者。虽然 接受性别肯定治疗的青春期前男孩或变性女孩不会产生精子，但会产生精子 睾丸中含有精原干细胞 SSC，具有产生精子的潜力。 MPI 位于 芝加哥和匹兹堡一直在为年轻患者冷冻未成熟的睾丸组织超过 十年后，人们预计这些组织可以在未来解冻并成熟以产生精子。每个 患者捐赠部分组织用于研究开发下一代技术，该技术将允许 他们利用自己的组织进行繁殖。我们将利用这些组织来获得对人类的基本了解 睾丸发育从新生儿到成年阶段。这将建立评估我们的基准 工程设计了三种支持离体精子发生的新型睾丸拟态系统。目标1 将使用微流体装置在空气/液体界面复制小鼠睾丸组织器官型培养物 以及静态 PDMS 顶部-transwell 系统，然后将该方法转化为人类睾丸组织。目标2将 建立小鼠和人类睾丸类器官，然后将其融合成细长的 曲细精管样结构。 Aim 3 将使用人类睾丸打印曲细精管状支架 细胞外基质 (htECM) 和猪睾丸 ECM (ptECM) 水凝胶作为生物墨水，然后用 小鼠和人类睾丸体细胞和生殖细胞。这些睾丸拟态系统将提供 对人类睾丸体细胞和生殖细胞发育的基本见解并建立实验 测试促进或阻止精子产生的毒理学或药物化合物或药物的平台。 首要目标是在一个或多个拟态系统中使人类睾丸组织成熟 离体产生具有受精能力的精子。