The Study and Manipulation of Male Germline Stem Cells

雄性生殖干细胞的研究和操作

• 批准号: RGPIN-2019-07124
• 负责人: Honaramooz, Ali
• 金额: $ 2.04万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682899
• 关键词: Study; Manipulation; Male; Germline; Stem

The testis is a prolific and efficient organ that produces hundreds of millions of sperm per day throughout the adult life. The foundation of this process is a very small group of cells known as male germline stem cells (MGSC). These stem cells have great potential because they are the only adult stem cells that can contribute genes to the next generation, thereby holding the key to male fertility. Manipulation of these stem cells can even lead to their differentiation into cells of other tissues (e.g., cardiac muscle or insulin-producing cells), raising hope that they can be used as an alternative source of adult stem cells for regenerative therapies. However, our knowledge of MGSC is limited because important questions regarding their unique characteristics and stem cell multipotency remain unanswered. ******The long-term objective of my research program is to uncover the fundamental aspects of MGSC biology and to harness their potential for the benefit of animal and human reproduction in Canada and beyond. Using neonatal pig testis tissue and cells as a model, we have made pioneering discoveries toward our long-term objectives. For instance, we have shown that when pig testis cells are injected under the back skin of mice they can regenerate functional testis tissue that is morphologically and functionally identical to intact testis tissue. These results support the use of this novel model to examine the factors required for normal formation of the testis or to test the potential effect of environmental toxicants on testis formation. Images of our recent results were among the top 20 selected nationwide by NSERC Science Exposed 2017 and 2018. ******NSERC-DG funding will enable the continuation of my research program on the biology and application of MGSC by: 1) examining testis tissue regeneration following incorporation into 3-dimensional printed tissue scaffolds and manipulation of hormones and growth factors thought to be involved in cell migration and tissue formation/regeneration; 2) examining cultured MGSC to explore their unique genes and biomarkers and stem cell multi-potency; and 3) investigating the culture conditions leading to exponential proliferation of MGSC for use in downstream applications, as well as for induction of spermatogenesis in vitro.******This is a novel and exciting research area with tremendous potential applications, including improvement of reproductive efficiency in livestock, manipulation of MGSC for use as a novel approach for producing genetically-modified (transgenic) farm animals, conservation of genetic material of endangered or prized animals, and potential use in restoring fertility of prepubertal boys undergoing cancer treatments.******This research will train 2 PhD, 2 MSc, and 5 summer undergraduate students, who upon completion will be well positioned to pursue further studies or careers in veterinary medicine or reproductive biology.**

睾丸是一个多产和高效的器官，在整个成年生活中每天产生数亿个精子。这一过程的基础是一小群被称为雄性生殖系干细胞(MGSC)的细胞。这些干细胞具有巨大的潜力，因为它们是唯一可以为下一代贡献基因的成年干细胞，从而掌握着男性生育的关键。对这些干细胞的操作甚至可以使它们分化为其他组织的细胞(例如，心肌或胰岛素产生细胞)，这增加了它们可以被用作再生疗法的成人干细胞的替代来源的希望。然而，我们对MGSC的了解有限，因为有关其独特特征和干细胞多能性的重要问题仍未得到解答。*我的研究计划的长期目标是揭示MGSC生物学的基本方面，并利用它们的潜力，造福于加拿大及其他地区的动物和人类繁殖。以新生的猪睾丸组织和细胞为模型，我们朝着我们的长期目标取得了开创性的发现。例如，我们已经证明，当猪睾丸细胞被注射到小鼠的背部皮肤下时，它们可以再生与完整的睾丸组织在形态和功能上相同的功能性睾丸组织。这些结果支持使用这一新的模型来检查睾丸正常形成所需的因素或测试环境毒物对睾丸形成的潜在影响。2017年和2018年，我们的最新结果图像跻身NSERC Science Exposed全国前20名。*NSERC-DG基金将通过以下方式继续我的MGSC生物学和应用研究计划：1)检测睾丸组织在三维打印组织支架中的结合以及对激素和生长因子的操作，这些激素和生长因子被认为参与细胞迁移和组织形成/再生；2)检测培养的MGSC，以探索其独特的基因和生物标记物以及干细胞的多能性；以及3)研究导致MGSC指数级增殖的培养条件，用于下游应用，以及在体外诱导精子发生。*这是一个新的、令人兴奋的研究领域，具有巨大的潜在应用，包括提高家畜的繁殖效率，操纵MGSC作为生产转基因(转基因)农场动物的新方法，保护濒危或珍贵动物的遗传物质，以及在恢复接受癌症治疗的青春期前男孩的生育能力方面的潜在应用。*这项研究将培养2名博士、2名硕士和5名暑期本科生。世界卫生组织在完成后将处于有利地位，可以在兽医或生殖生物学方面继续深造或从事职业。**