Molecular communications between Sertoli cells and extracellular vesicles of milk

支持细胞和牛奶细胞外囊泡之间的分子通讯

• 批准号: 10937312
• 负责人: Amy T Desaulniers
• 金额: $ 17.67万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-18 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10937312
• 关键词: Affect; Age Months; Apoptosis; Binding; Biological; Biological Availability; Body Fluids; Breastfed infant; Cardiovascular system; Cell Communication; Cell Proliferation; Cell Survival; Cell division; Cells; Communication; Consumption; Development; Diet; Dietary Intervention; Digestion; Discipline of Nursing; Disease; Distant; Docking; Early identification; Ejaculation; Endocytosis; Family suidae; Fertility; Goals; Growth; Growth and Development function; Health Benefit; Hour; Human Milk; In Vitro; Infant; Intervention; Intestines; Knowledge; Label; Learning; Male Infertility; Male Nurses; Milk; Mitosis; Molecular; Morbidity - disease rate; Mus; Nebraska; Neonatal; Nursing infant; Organ; Phase; Population; Production; Proliferating; Proteins; Puberty; RNA; Reproductive Health; Risk; Sperm Count Procedure; Supplementation; Supporting Cell; Testis; Tissues; Travel; absorption; cell type; comparison control; dietary; exosome; extracellular vesicles; improved; infancy; inhibitor; male; male fertility; male health; men; mortality; nanoparticle; neonate; nutrition; obesity prevention; offspring; sertoli cell; sperm cell

Sperm counts in men have declined by 52% since 1971, demonstrating a reproductive health crisis. Furthermore, male infertility predicts an increased risk of morbidity and early mortality. Our long-term goal is to identify early nutritional interventions that promote the fertility and health of men. Interestingly, consumption of mother’s milk enhances testicular growth, development, and subsequent sperm production of offspring. For example, nursed infants had 20% larger testes compared to formula fed babies and male pigs nursed for 48 hours had a 34% greater number of Sertoli cells compared to formula-fed littermates. Sertoli cells are a critical support cell for developing sperm in the testis and the number of Sertoli cells is established during infancy and determines testicular size. Thus, larger testes and more Sertoli cells in nursed males suggests greater sperm production capacity after puberty. Indeed, male piglets who consumed more milk during infancy produced 17 billion more sperm cells per ejaculate compared with littermates who consumed less milk as neonates. The biological mechanisms that connect nursing with improved testis development remain undefined. However, a candidate regulator of this interaction is the milk exosome. Exosomes are natural nanoparticles within body fluids that facilitate cell-to-cell communication by transferring bioactive regulatory cargos (e.g., proteins, RNAs) from donor to recipient cells. We recently learned that milk exosomes survive digestion, are absorbed by the neonatal intestine, and travel via the circulatory system to distant neonatal organs where they unload their regulatory cargo and profoundly affect tissue function. Thus, milk exosomes are bioavailable to neonatal tissues, including the testis. Notably, milk exosomes are abundant in milk but absent in formula and male mice fed a diet depleted of milk exosomes sired 50% fewer offspring compared to controls fed diets containing milk exosomes, suggesting that milk exosomes influence male fertility. The overall objective for this project is to determine the mechanisms and result of milk exosome and Sertoli cell interactions. The central hypothesis of this project is that milk exosomes deliver regulatory cargo to Sertoli cells via endocytosis to promote proliferation. In Aim 1, we will utilize an in vitro approach and examine the molecular interaction of fluorescently-labeled porcine milk exosomes and/or their cargo with porcine Sertoli cells in the presence or absence of endocytosis inhibitors. In Aim 2, we will assess Sertoli cell proliferation and viability in the presence or absence of milk exosomes. This knowledge is critical because extensive testicular growth and development occurs during early infancy in breastfed infants but only 25% of babies exclusively receive mother’s milk through 6 months of age. Interventions (e.g., exosome supplementation in formula) could improve nutrition for 1.9 million male infants annually leading to population-level fertility and health benefits for men.

自 1971 年以来，男性精子数量下降了 52%，显示出生殖健康危机。此外，男性不育预示着发病和早期死亡的风险增加。我们的长期目标是确定促进男性生育能力和健康的早期营养干预措施。有趣的是，食用母乳可以促进睾丸的生长、发育以及随后后代精子的产生。例如，与配方奶喂养的婴儿相比，哺乳的婴儿的睾丸大 20%；与配方奶喂养的同窝仔猪相比，喂养 48 小时的公猪的支持细胞数量增加了 34%。支持细胞是睾丸中精子发育的关键支持细胞，支持细胞的数量在婴儿期就已确定，并决定睾丸的大小。因此，哺乳男性的睾丸较大，支持细胞较多，表明青春期后精子产生能力较强。事实上，与新生儿期消耗较少牛奶的同窝仔猪相比，在婴儿期消耗较多牛奶的雄性仔猪每次射精产生的精子细胞数量要多 170 亿个。将护理与改善睾丸发育联系起来的生物学机制仍不清楚。然而，这种相互作用的候选调节剂是乳外泌体。外泌体是体液中的天然纳米颗粒，通过将生物活性调节物质（例如蛋白质、RNA）从供体细胞转移到受体细胞来促进细胞间的通讯。我们最近了解到，乳汁外泌体能够在消化后存活下来，被新生儿肠道吸收，并通过循环系统到达远处的新生儿器官，在那里它们卸载其调节物质并深刻影响组织功能。因此，乳汁外泌体对新生儿组织（包括睾丸）具有生物利用度。值得注意的是，牛奶中含有丰富的乳外泌体，但配方奶粉中却缺乏乳外泌体，并且与饲喂含有乳外泌体的饮食的对照小鼠相比，饲喂缺乏乳外泌体的饮食的雄性小鼠产生的后代减少了 50%，这表明乳外泌体影响雄性生育能力。该项目的总体目标是确定乳汁外泌体和支持细胞相互作用的机制和结果。该项目的中心假设是乳外泌体通过内吞作用将调节物质传递至支持细胞以促进增殖。在目标 1 中，我们将利用体外方法，检查荧光标记的猪乳外泌体和/或其货物与猪支持细胞在存在或不存在内吞作用抑制剂的情况下的分子相互作用。在目标 2 中，我们将评估支持细胞在存在或不存在乳外泌体的情况下的增殖和活力。这一知识至关重要，因为母乳喂养的婴儿在婴儿期早期睾丸会大量生长和发育，但只有 25% 的婴儿在 6 个月大时完全接受母乳。干预措施（例如，在配方奶粉中添加外泌体）每年可以改善 190 万男婴的营养，从而提高男性的人口生育率和健康水平。