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，男性的精子数量下降了52%，表明生殖健康危机。此外，男性不育症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早期营养干预措施，促进男性的生育力和健康。有趣的是，母乳的消费促进睾丸的生长，发育和随后的后代精子生产。例如，与配方奶喂养的婴儿相比，喂养婴儿的睾丸大20%，与配方奶喂养的同窝出生的婴儿相比，喂养48小时的雄性猪的支持细胞数量多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建立，并决定睾丸的大小。因此，较大的睾丸和更多的支持细胞在哺乳男性表明更大的精子生产能力后，青春期。事实上，在婴儿期摄入更多牛奶的雄性小猪每次射精产生的精子细胞比新生儿时摄入较少牛奶的同窝仔多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明确。然而，这种相互作用的候选调节剂是乳外泌体。外来体是体液内的天然纳米颗粒，其通过转移生物活性调节货物（例如，蛋白质，RNA）从供体细胞到受体细胞。我们最近了解到，牛奶外泌体在消化中存活，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，在那里它们卸下其调节货物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）是生物可利用的。值得注意的是，牛奶外泌体在牛奶中丰富，但在配方奶粉中不存在，与喂食含有牛奶外泌体的饮食的对照组相比，喂食牛奶外泌体的饮食的雄性小鼠的后代少50%，这表明牛奶外泌体影响雄性生育力。本项目的总体目标是确定牛奶外泌体和Sertoli细胞相互作用的机制和结果。该项目的中心假设是乳汁外泌体通过内吞作用将调节性货物递送至支持细胞以促进增殖。在目标1中，我们将利用体外方法，并检查荧光标记的猪乳汁外泌体和/或其货物与猪支持细胞在存在或不存在内吞抑制剂的情况下的分子相互作用。在目标2中，我们将评估在存在或不存在乳汁外泌体的情况下支持细胞增殖和活力。这方面的知识是至关重要的，因为广泛的睾丸生长和发育发生在婴儿早期母乳喂养的婴儿，但只有25%的婴儿完全接受母乳通过6个月的年龄。干预措施（例如，在配方奶粉中添加外来体）每年可改善190万男婴的营养，从而为男性带来人口水平的生育和健康益处。