extracellular vesicles

Circulating extracellular vesicles as functional indicators of maternal mental and physical health in pregnancy and postpartum

Women with high levels of adverse childhood experiences (ACEs) are at significantly greater risk for negative health outcomes in pregnancy and postpartum, including gestational diabetes, PTB, and depressed mood. However, we still lack biomarkers or a sufficient understanding of causal mechanisms. Extracellular vesicles (EVs) are one of the most dynamic and abundant biological signals secreted into maternal circulation, largely produced by the placenta – where levels increase 4-5-fold during pregnancy. Similarly, removal of the placenta at delivery produces a dramatic drop in maternal EV concentration. Across species, we and others have identified significant EV changes during pregnancy associated with homeostatic regulation, including glucose and glucocorticoid levels, supporting key roles for EVs in maternal health. However, longitudinal studies in human pregnancy and postpartum have not been conducted. We know little as to the mechanisms controlling EV secretion or the roles for EVs in maternal pregnancy and postpartum health. Our decade’s long work identified the X-linked gene, O-glycosyltransferase (OGT), in mouse and human placenta as a master gage of the maternal milieu, where OGT regulation of annexin A1 (AA1) is key to EV cargo loading and secretion from the placenta. We recently reported that placental OGT levels positively correlate with maternal EV concentration. How this association may contribute toward postpartum health, including regulating maternal stress physiology and mood in humans is not known. We hypothesize that increased ACEs, similar to stress in preclinical models, are negatively associated with a cell’s ability to secrete EVs important to maintain homeostasis in the face of the challenges of pregnancy and postpartum, producing an increasingly unhealthy state. Therefore, the goals of these proposed studies in both mice and humans are as follows: 1) To identify cellular mechanisms involved in EV secretion important to maternal health outcomes utilizing the placenta as a tool to genetically target OGT in mice and examine maternal homeostatic control related to EV concentration and composition during pregnancy; 2) To examine the functional ability for a dynamic elevation in maternal EV concentration to improve homeostatic regulation in pregnancy and postpartum using chemogenetic activation (DREADDs) of placenta trophoblast cells in pregnancy, and by EV transfer by tail vein injection postpartum; and 3) To examine in women changes in maternal EVs in a longitudinal pregnancy and postpartum study in association with maternal glucose and cortisol changes, we will examine markers of physical (glucose challenge test), HPA stress (hair cortisol & stress- stimulated salivary cortisol) and psychological (Hamilton Rating Scale for Depression, Perceived Stress Scale) health across pregnancy and the postpartum period in 150 healthy women with varying degrees of exposure to ACEs as measured using the ACE Questionnaire (ACE-Q).

Programming Offspring Metabolism: The Role of Milk Extracellular Vesicles in Fat Development

SUMMARY Obesity is a global health crisis, contributing significantly to the prevalence of metabolic disorders, cardiovascular diseases, and various chronic conditions. A growing body of evidence suggests that maternal obesity during pregnancy and lactation can predispose offspring to obesity and metabolic dysfunction later in life. However, the mechanisms by which maternal obesity programs these adverse outcomes in offspring remain poorly understood. Breast milk is not only a source of essential nutrients but also contains bioactive components, including extracellular vesicles (EVs), which play crucial roles in cellular communication and development. Recent studies have shown that EVs can survive digestion and enter the infant’s circulation, influencing immune and metabolic development. Despite the established link between maternal obesity and altered breast milk composition, no study has investigated the role of milk-derived EVs (mEVs) in programming offspring fat development and metabolism. Understanding this novel pathway could revolutionize our approach to preventing intergenerational transmission of obesity. Our preliminary studies using a mouse model of maternal high-fat diet-induced obesity revealed significant alterations in mEV biogenesis and cargo composition, including changes in specific miRNAs. Oral administration of mEVs from obese dams to neonatal mice increased adiposity and impaired lipid metabolism, indicating that mEVs are crucial in modulating fat development and metabolic pathways in offspring. Several key miRNAs found in mouse mEVs are conserved in human milk EVs, highlighting the potential translational relevance of our findings to human health. We hypothesize that mEVs are critical mediators of maternal obesity’s programming effects on offspring metabolism and adiposity. In specific aim 1, we will use mouse models and advanced molecular techniques (miRNA sequencing, proteomics, and lipidomics) to characterize how maternal obesity affects mEV biogenesis and the composition of their bioactive cargo. We will also evaluate how maternal dietary intake, independent of obesity, influences mEV composition. Specific aim 2 will define the programming effects of mEVs on offspring energy metabolism and obesity. In addition, we will explore whether human milk EVs from lean and obese mothers exert similar programming effects on fat development and metabolism in a mouse model. This R21 application embodies a high-risk, high-reward approach to obesity research. It ventures into uncharted territory by proposing that mEVs are novel regulators of metabolic programming, a concept that has not been explored in prior studies. The potential reward is substantial: discovering a new mechanism by which maternal obesity influences offspring health could fundamentally shift our understanding of early-life metabolic programming and lead to innovative strategies for obesity prevention. If successful, this research could open a new field of study with broad implications for maternal and child health.

The role of extracellular vesicles in sickness and in health

Virus-like intercellular communication in the nervous system

The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and mediates various forms of synaptic plasticity. We recently discovered that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses such as HIV. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system that may underlie cognition and memory.

Acute intralesional application of extracellular vesicles improves outcomes in a rat model of traumatic spinal cord injury

Application of extracellular vesicles in a 3D blood-brain barrier spheroid model

Brain region specificity of astrocyte-derived extracellular vesicles: preservation of mitochondrial function in a cellular model of Parkinson’s disease

Characterization of extracellular vesicles released from spinal cord astrocytes of late symptomatic SOD1G93A mouse model of amyotrophic lateral sclerosis

Dysregulation Of Brain-Derived Neurotrophic Factor Receptor In Alzheimer’s Disease Is Mirrored In Extracellular Vesicles

Effect of APOE ε4 allele on redox signature in circulating extracellular vesicles from cognitively impaired with no dementia participants converted to Alzheimer’s disease

Extracellular vesicles from human iPSC-derived neural stem cells alleviate microglial response and cognitive impairments in a chronic neuroinflammation model

Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats by reducing NF-κB activation via TGFβ receptor activation

Extracellular vesicles underlie cell-type-specific crosstalk during human cortical development

Functional recovery caused by human adipose tissue mesenchymal stem cell-derived extracellular vesicles administered 24h after stroke in normotensive rats and some differences to hypertensive rats

A miRNA fingerprint in Plasma-derived extracellular vesicles of hSOD1G93A transgenic swine

Role of neuron-derived extracellular vesicles in synaptic plasticity

Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation

Characterizing nerve-derived extracellular vesicles: Potentials and pitfalls

FENS Forum 2024

Deciphering the role of specific membrane transporters in extracellular vesicles

FENS Forum 2024

Endogenous alpha-Synuclein is essential for the transfer of pathology by exosome-enriched extracellular vesicles, following inoculation with preformed fibrils in vivo

FENS Forum 2024

Extracellular vesicles: An exploration into the bi-directional crosstalk of endothelial cells and astrocytes at the blood-brain barrier

FENS Forum 2024

Extracellular vesicles from hypothalamic astrocytes modify transcription factors of the leptin signaling pathway in proopiomelanocortin (POMC) neurons

FENS Forum 2024

Extracellular vesicles from mesenchymal stem cells alter gut microbiota and improve neuroinflammation and motor impairment in rats with mild liver damage

FENS Forum 2024

Extracellular vesicles from MSCs reverse neuroinflammation in cerebellum and restore motor coordination in hyperammonemic rats

FENS Forum 2024

Extracellular vesicles from poly I:C-infected airway epithelial cells mediate viral signaling in microglia: Implications for neuroinflammation

FENS Forum 2024

Extracellular vesicles and transmission of α-synuclein pathology: From cellular models to diagnostic applications

FENS Forum 2024

IL-4-induced microglia-derived small extracellular vesicles exhibit cytoprotective effects against LPS-induced microglial damage through miR-191-5p

FENS Forum 2024

Involvement of glioblastoma-derived extracellular vesicles in promoting endothelial cell remodelling: Implications for glioblastoma tumour progression

FENS Forum 2024

Loss of neuroprotection in Alzheimer’s disease: Shedding light on BDNF receptor cleavage and its mirroring in extracellular vesicles

FENS Forum 2024

Mechanisms of spinocerebellar ataxia type 2 pathogenesis: Insights from small extracellular vesicles

FENS Forum 2024

Plasma extracellular vesicles from hyperammonemia rats induce neuroinflammation in the hippocampus and cognitive impairment in control rats

FENS Forum 2024

Post-transcriptional regulation of neurodevelopment mediated by extracellular vesicles

FENS Forum 2024

Therapeutic effect of extracellular vesicles derived from mesenchymal stem cells in amyotrophic lateral sclerosis

FENS Forum 2024