The role of biomechanical stress in extracellular vesicle formation, composition and activity

Thompson, Will; Papoutsakis, Eleftherios T.

doi:10.1016/j.biotechadv.2023.108158

Cited by 21 publications

(5 citation statements)

References 239 publications

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“…The impact of mechanical force on in vivo production of extracellular vesicles has not been a major focus of the EV field, although a range of studies have considered force consequences (such as fluid shear responses, stretch) in cultured cells. Overall, however, EV biogenesis and uptake appear to be markedly influenced by biomechanical force type, magnitude, and duration 81 . At the same time, the neurodegeneration field has generated myriad studies linking Alzheimer’s disease susceptibility and AD pathology signatures such as extracellular accumulation of amyloid-β protein and/or intracellular accumulation of tau as outcomes of mechanical stress-based stimuli such as traumatic brain injury, arterial hypertension, and normal pressure hydrocephalus 82,83 .…”

Section: Discussionmentioning

confidence: 94%

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

Wang,

Guasp,

Salam

et al. 2023

Preprint

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Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate extrusion of large vesicles, such as exophers produced by proteostressedC. eleganstouch neurons, are poorly understood. Here we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from theC. elegansALMR neuron peaks at adult day 2 or 3, coinciding with theC. elegansreproductive peak. Genetic disruption ofC. elegansgermline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

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Section: Discussionmentioning

confidence: 94%

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

Wang,

Guasp,

Salam

et al. 2023

Preprint

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“…Our previous study using this bioreactor system for the generation of hMSC‐derived EVs shows that this system is reproducible and scalable (from 0.1 to 0.5 L) (Jeske et al., 2023 ). In addition, the effect of shear stress on the production of large EVs may cause a large size distribution of EVs (Thompson & Papoutsakis, 2023 ; Thone & Kwon, 2020 ). It is postulated that this effect is related to the shear stress levels exerted on the cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle biogenesis of three‐dimensional human pluripotent stem cells in a novel Vertical‐Wheel bioreactor

Muok,

Sun,

Esmonde

et al. 2024

J of Extracellular Bio

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Extracellular vesicles (EVs) secreted by human‐induced pluripotent stem cells (hiPSCs) have great potential as cell‐free therapies in various diseases, including prevention of blood–brain barrier senescence and stroke. However, there are still challenges in pre‐clinical and clinical use of hiPSC‐EVs due to the need for large‐scale production of a large quantity. Vertical‐Wheel bioreactors (VWBRs) have design features that allow the biomanufacturing of hiPSC‐EVs using a scalable aggregate or microcarrier‐based culture system under low shear stress. EV secretion by undifferentiated hiPSCs expanded as 3‐D aggregates and on Synthemax II microcarriers in VWBRs were investigated. Additionally, two types of EV collection media, mTeSR and HBM, were compared. The hiPSCs were characterized by metabolite and transcriptome analysis as well as EV biogenesis markers. Protein and microRNA cargo were analysed by proteomics and microRNA‐seq, respectively. The in vitro functional assays of microglia stimulation and proliferation were conducted. HiPSCs expanded as 3‐D aggregates and on microcarriers had comparable cell number, while microcarrier culture had higher glucose consumption, higher glycolysis and lower autophagy gene expression based on mRNA‐seq. The microcarrier cultures had at least 17–23 fold higher EV secretion, and EV collection in mTeSR had 2.7–3.7 fold higher yield than HBM medium. Microcarrier culture with mTeSR EV collection had a smaller EV size than other groups, and the cargo was enriched with proteins (proteomics) and miRNAs (microRNA‐seq) reducing apoptosis and promoting cell proliferation (e.g. Wnt‐related pathways). hiPSC‐EVs demonstrated the ability of stimulating proliferation and M2 polarization of microglia in vitro. HiPSC expansion on microcarriers produces much higher yields of EVs than hiPSC aggregates in VWBRs. EV collection in mTeSR increases yield compared to HBM. The biomanufactured EVs from microcarrier culture in mTeSR have exosomal characteristics and are functional in microglia stimulation, which paves the ways for future in vivo anti‐aging study.

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“…Our investigation revealed that phenotypic switching with increased IFSS stimulation acts as an upstream regulator of pro-calcified EVs secretion. Besides, other research indicated that the mechanism underlying the observed correlations between mechanical stress and EV biogenesis is complex and depends significantly on both the parent cell type and the nature of the applied stress 61 . Therefore, the relationship between shear stress and the release of EVs remains a focal point for future research in cardiovascular diseases 62 .…”

Section: Discussionmentioning

confidence: 99%

Interstitial Fluid Shear Stress Induces the Synthetic Phenotype Switching of VSMCs to Release Pro-calcified Extracellular Vesicles via EGFR-MAPK-KLF5 Pathway

Gao,

Gu,

et al. 2024

Int. J. Biol. Sci.

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Phenotypic switching (from contractile to synthetic) of vascular smooth muscle cells (VSMCs) is essential in the progression of atherosclerosis. The damaged endothelium in the atherosclerotic artery exposes VSMCs to increased interstitial fluid shear stress (IFSS). However, the precise mechanisms by which increased IFSS influences VSMCs phenotypic switching are unrevealed. Here, we employed advanced numerical simulations to calculate IFSS values accurately based on parameters acquired from patient samples. We then carefully investigated the phenotypic switching and extracellular vesicles (EVs) secretion of VSMCs under various IFSS conditions. By employing a comprehensive set of approaches, we found that VSMCs exhibited synthetic phenotype upon atherosclerotic IFSS. This synthetic phenotype is the upstream regulator for the enhanced secretion of pro-calcified EVs. Mechanistically, as a mechanotransducer, the epidermal growth factor receptor (EGFR) initiates the flow-based mechanical cues to MAPK signaling pathway, facilitating the nuclear accumulation of the transcription factor krüppel-like factor 5 (KLF5). Furthermore, pharmacological inhibiting either EGFR or MAPK signaling pathway blocks the nuclear accumulation of KLF5 and finally results in the maintenance of contractile VSMCs even under increased IFSS stimulation. Collectively, targeting this signaling pathway holds potential as a novel therapeutic strategy to inhibit VSMCs phenotypic switching and mitigate the progression of atherosclerosis.

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The role of biomechanical stress in extracellular vesicle formation, composition and activity

Cited by 21 publications

References 239 publications

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

Extracellular vesicle biogenesis of three‐dimensional human pluripotent stem cells in a novel Vertical‐Wheel bioreactor

Interstitial Fluid Shear Stress Induces the Synthetic Phenotype Switching of VSMCs to Release Pro-calcified Extracellular Vesicles via EGFR-MAPK-KLF5 Pathway

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