Cellular Mechanisms of Chemotherapy-induced Male Infertility: Stem Cell or Niche?

化疗引起男性不育的细胞机制：干细胞还是利基？

• 批准号: 8636803
• 负责人: Kyle Edwin Orwig
• 金额: $ 57.62万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636803
• 关键词: Address; Age; Anatomy; Animal Model; Autologous; Biological Preservation; Biopsy; Bone Marrow Transplantation; Busulfan; Cancer Survivor; Cancer Survivorship; Cell Culture Techniques; Cell Survival; Cell Therapy; Cell physiology; Cell surface; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Cyclophosphamide; Data; Defect; Diagnosis; Dose; Endocrine; Environment; Exposure to; Fertility; Follicle Stimulating Hormone; Foundations; Freezing; Future; Gene Expression; Gonadal structure; Health; Hematopoietic Stem Cell Transplantation; High Dose Chemotherapy; Human; Hypothalamic structure; Infertility; Knowledge; Lead; Life; Luteinizing Hormone; Macaca mulatta; Male Infertility; Malignant Neoplasms; Mediating; Micromanipulation; Mind; Modeling; Monkeys; Morphology; Natural regeneration; Non-Malignant; Nuclear; Nude Mice; Patients; Physiology; Pituitary Gland; Plants; Population; Precocious Puberty; Pregnancy; Primates; Production; Proliferating; Property; Puberty; RNA Sequences; Radiation; Recovery; Regulation; Relative (related person); Research; Research Institute; Rodent; Safety; Schedule; Signal Pathway; Signal Transduction; Spermatogenesis; Spermatogonia; Staining method; Stains; Stem cell transplant; Stem cells; Techniques; Technology; Testicular Tissue; Testing; Testis; Testosterone; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Translating; Transplantation; United States; Walkers; Whole-Body Irradiation; Woman; Xenograft procedure; base; boys; cancer therapy; chemotherapy; childhood cancer survivor; clinically relevant; conditioning; cytotoxic; experience; high risk; innovation; insight; leydig interstitial cell; male; men; nonhuman primate; novel; patient population; pre-clinical; preclinical study; prepuberty; programs; regenerative; sertoli cell; sperm cell; stem cell niche; stem cell population; stem cell technology; stem cell therapy

DESCRIPTION (provided by applicant): Spermatogonial stem cells (SSCs) are at the foundation of spermatogenesis and may have application for treating some cases of male infertility. High dose chemotherapy treatments for cancer and other non-malignant conditions can cause azoospermia, which may be due to a depletion of the SSC pool. If that is the case and the testicular environment (SSC niche) is functionally intact, then SSC transplantation may constitute a cell based therapy for restoring fertility in male cancer survivors. Theoretically, SSCs can be isolated via biopsy and cryopreserved prior to cancer treatment and then reintroduced into the testis after cure to regenerate spermatogenesis. The proof in principle for this approach is already established in several animal models, including recent progress from our lab in primates. Therefore, it is tempting to speculate that SSC transplantation might be translated to the human fertility clinic. This option may be particularly appropriate for prepubert boys who are not yet producing sperm and have no options to preserve their future fertility. With this in mind, several academic centers around the world, including our Fertility Preservation Program in Pittsburgh, are cryopreserving testicular tissues for boys in anticipation that SSCs can be used in the future to restore fertility. Pre-clinical studies are critically needed to demonstrate the feasibility of SSC transplantation in a model that is relevant to human anatomy and physiology as well as the target prepubertal patient population. In this application, we will treat prepubertal rhesus macaques with a clinically relevant high-dose alkylating chemotherapy regimen (BuCy2) that is expected to cause azoospermia. The SSC pool in nonhuman primate and human testes is comprised of Adark and Apale spermatogonia, but the relative regenerative potential of these morphologically distinct spermatogonial subtypes are not known. In Aim 1 we will evaluate and compare the stem cell properties of Adark and Apale spermatogonia, which will impact strategies to manipulate these cells for therapeutic purposes. Aims 2 will examine the effects of BuCy2 on the stem cell pool and somatic/endocrine environment (stem cell niche) of prepubertal testes. Aim 3 will model the clinical scenario of the prepubertal patient that is at high risk for azoospermia due to BuCy2 conditioning prior to hematopoietic stem cell transplantation. In that model, we will perform autologous SSC transplantation from frozen/thawed testicular cells. Fundamental knowledge generated in aims 1 and 2 could lead to novel SSC enrichment and niche therapy strategies that will be applied in Aim 3 to enhance spermatogenesis from endogenous or transplanted SSCs.

描述（由申请人提供）：精子干细胞（SSC）是精子发生的基础，可能应用于治疗某些男性不育症。高剂量的化学疗法治疗癌症和其他非恶性疾病可能会导致植物植物，这可能是由于SSC池的耗竭。如果是这种情况，并且睾丸环境（SSC利基）在功能上是完整的，那么SSC移植可能构成基于细胞的疗法，用于恢复男性癌症幸存者的生育能力。从理论上讲，可以通过活检和冷冻保存在癌症治疗前分离SSC，然后在治愈后重新引入睾丸以再生精子发生。原则上的证据已经在几种动物模型中建立了，包括我们实验室的最新进展。因此，很容易推测可以将SSC移植转化为人类生育诊所。此选项可能特别适合尚未生产精子并且没有保留未来生育能力的Prepubert Boys。考虑到这一点，世界各地的几个学术中心，包括我们在匹兹堡的生育保存计划，正在为男孩的冷冻水平睾丸组织提供预期，即将将来使用SSC来恢复生育能力。需要进行临床前研究，以证明与人类解剖学和生理学以及靶青春期前患者人群有关的模型中SSC移植的可行性。在此应用中，我们将使用临床相关的高剂量烷基化化学疗法方案（BUCY2）来治疗前猕猴，该方案预计会引起Azoospermia。非人类灵长类动物和人类睾丸中的SSC库由Adark和Apale精子组成，但是这些形态上不同的精子亚型的相对再生潜力尚不清楚。在AIM 1中，我们将评估和比较Adark和Apale精子的干细胞特性，这将影响以治疗目的操纵这些细胞的策略。 AIM 2将检查Bucy2对青春期前睾丸的干细胞池和体细胞环境（干细胞生态位）的影响。 AIM 3将建模为前青春期患者的临床情况 在造血干细胞移植之前，由于Bucy2调节而导致的无植物症的高风险。在该模型中，我们将从冷冻/解冻的睾丸细胞中进行自体SSC移植。目标1和2中产生的基本知识可能会导致新型的SSC富集和利基治疗策略，这些策略将用于AIM 3中，以增强内源性或移植的SSC的精子发生。