Molecular communications between Sertoli cells and extracellular vesicles of milk

University Of Nebraska Lincoln, Lincoln NE

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Abstract

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.