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

基本信息

  • 批准号:
    10937312
  • 负责人:
  • 金额:
    $ 17.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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率和早期死亡的风险增加。我们的长期目标是确定能够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、发育和后代的精子产量。例如,母乳喂养的婴儿睾丸比配方奶喂养的婴儿大20%,而喂养48小时的雄性猪的支持细胞数量比配方奶喂养的幼崽多34%。支持细胞是睾丸中精子发育的重要支持细胞,支持细胞的数量在婴儿期形成,并决定睾丸的大小。因此,在哺乳的雄性中,更大的睾丸和更多的支持细胞表明在青春期后更大的精子生产能力。事实上,在婴儿期摄入更多牛奶的雄性仔猪每次射精比在新生儿时期摄入较少牛奶的同伴多产生170亿个精子细胞。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因子是乳外泌体。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(如蛋白质、rna)从供体细胞转移到受体细胞,促进细胞间的通讯。我们最近了解到,乳外泌体在消化过程中存活下来,被新生儿肠道吸收,并通过循环系统到达遥远的新生儿器官,在那里它们卸下调节货物,并深刻地影响组织功能。因此,乳外泌体对包括睾丸在内的新生儿组织具有生物可利用性。值得注意的是,牛奶中含有丰富的乳外泌体,但配方奶中却没有。与喂食含有乳外泌体的对照组相比,喂食缺乏乳外泌体的雄性小鼠的后代数量减少了50%,这表明乳外泌体影响了雄性的生育能力。该项目的总体目标是确定乳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向支持细胞递送调节货物以促进增殖。在目标1中,我们将利用体外方法,在存在或不存在内吞抑制剂的情况下,检测荧光标记的猪乳外泌体和/或其货物与猪支持细胞的分子相互作用。在目标2中,我们将评估在乳外泌体存在或不存在的情况下支持细胞的增殖和活力。这一知识是至关重要的,因为在母乳喂养的婴儿早期,睾丸会广泛生长和发育,但只有25%的婴儿在6个月大之前完全接受母乳。干预措施(例如,在配方奶粉中添加外泌体)每年可改善190万男婴的营养,从而提高人口水平的生育率,并有利于男子的健康。

项目成果

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