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 这是一种多PI，多机构的赠款，用于开发模仿人类睾丸的生理模拟系统 发育和精子谱系发展，离体。化学疗法和放射治疗 针对跨性别患者的癌症或性别肯定治疗可能会导致不育。成年患者有 在治疗之前，可以在将来融化并用于实现的治疗前的冷冻鸡蛋或精子的选择 具有标准辅助生殖技术的怀孕，包括IVF。这些选项不可用 所有成年患者或无法产生成熟卵或精子的青春期前患者。虽然 肯定性别治疗的青春期前男孩或变性女孩没有产生精子，他们确实会 在其睾丸中具有精子干细胞SSC，具有产生精子的潜力。 MPIS 芝加哥和匹兹堡一直在冷冻保存年轻患者的未成熟睾丸组织，超过 十年的预期，这些组织将来可以解冻并成熟以产生精子。每个 患者捐赠了一部分组织以进行研究，以开发下一代技术 他们使用组织进行繁殖。我们将使用这些组织来获得对人类的基本见解 睾丸从新生儿到成人生活阶段的发展。这将建立基准来评估我们的 进步工程，三个支持精子发生的新型睾丸生理模拟系统，离体。目标1 将使用微流体设备在空气/液体界面上复制小鼠睾丸组织器官培养物 在将方法转换为人睾丸组织之前，静态的PDMS屋顶横向系统。 AIM 2意志 建立小鼠和人睾丸类器官，然后将其诱导融合成伸长 类似小管的结构。 AIM 3将使用人类睾丸打印像脚手架一样的生精管 细胞外基质（HTECM）和猪睾丸ECM（PTECM）水凝胶作为生物学 小鼠和人睾丸体细胞和生殖细胞。这些睾丸生理模拟系统将提供 对人睾丸体细胞和生殖细胞发育的基本见解并建立实验 测试促进或预防精子产生的毒理学或药物化合物或药物的平台。 总体目标是在这些生理模拟系统中的一个或多个中成熟的人类睾丸组织 产生受精的精子，离体。