Granulosa cell-derived extracellular vesicles mitigate the detrimental impact of thermal stress on bovine oocytes and embryos

Abstract

Climate change-induced global warming results in rises in body temperatures above normal physiological levels (hyperthermia) with negative impacts on reproductive function in dairy and beef animals. Extracellular vesicles (EVs), commonly described as nano-sized, lipid-enclosed complexes, harnessed with a plethora of bioactive cargoes (RNAs, proteins, and lipids), are crucial to regulating processes like folliculogenesis and the initiation of different signaling pathways. The beneficial role of follicular fluid-derived EVs in inducing thermotolerance to oocytes during in vitro maturation (IVM) has been evidenced. Here we aimed to determine the capacity of in vitro cultured granulosa cell-derived EVs (GC-EVs) to modulate bovine oocytes’ thermotolerance to heat stress (HS) during IVM. Moreover, this study tested the hypothesis that EVs released from thermally stressed GCs (S-EVs) shuttle protective messages to provide protection against subsequent HS in bovine oocytes. For this, sub-populations of GC-EVs were generated from GCs subjected to 38.5°C (N-EVs) or 42°C (S-EVs) and supplemented to cumulus-oocyte complexes (COCs) matured in vitro at the normal physiological body temperature of the cow (38.5°C) or HS (41°C) conditions. Results indicate that S-EVs improve the survival of oocytes by reducing ROS accumulation, improving mitochondrial function, and suppressing the expression of stress-associated genes thereby reducing the severity of HS on oocytes. Moreover, our findings indicate a carryover impact from the addition of GC-EVs during oocyte maturation in the development to the blastocyst stage with enhanced viability.

Advancements in Genetic Biomarkers and Exogenous Antioxidant Supplementation for Safeguarding Mammalian Cells against Heat-Induced Oxidative Stress and Apoptosis

“…Additionally, Khan et al [ 47 ] reported that HS significantly compromises granulosa cells, leading to suboptimal oocyte development. This is further supported by studies that found HS compromises the mRNA expression levels of Moloney sarcoma oncogene (MOS), growth factor 9 (GDF9), and POU domain, class 5, transcription factor 1 (POUF51), which are crucial for oocyte development and competence, ultimately resulting in poor-quality oocytes and impaired embryonic development [ 60 , 61 , 70 , 71 , 72 ]. Figure 1 demonstrates the adverse impact of heat stress on phenotypic traits related to mammalian reproductive traits.…”

“…Furthermore, HS exerts detrimental effects on follicle quality and hormonal equilibrium, contributing to a decline in estrus [ 54 , 55 , 56 , 57 , 58 ]. Specifically, granulosa cells responsible for estradiol production are adversely affected by HS, resulting in decreased estradiol production and subsequent disruption of the estrous cycle in cattle [ 59 , 60 , 61 ]. HS has also been shown to influence corticoid levels, luteinizing hormone (LH), and plasma progesterone in cattle, with alterations in hypothalamus and pituitary gland function leading to changes in the secretion of reproductive hormones [ 9 , 62 , 63 , 64 , 65 , 66 ].…”

MicroRNA Nano-Shuttles: Engineering Extracellular Vesicles as a Cutting-Edge Biotechnology Platform for Clinical Use in Therapeutics

“…It is well-documented that the expression level of particular miRNAs are key during development [29,30] and stress responses [31,32], and that EVs play an important role in transferring miRNA cargoes between cells [33]. Alterations in the release and uptake of EVs are associated with pathologies including cancer [34] and cellular stress [32,[35][36][37][38][39].…”