Role of ATP in Extracellular Vesicle Biogenesis and Dynamics

Lombardi, Marta; Gabrielli, Martina; Adinolfi, Elena; Verderio, Claudia

doi:10.3389/fphar.2021.654023

Cited by 39 publications

(39 citation statements)

References 90 publications

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“…Furthermore, the increase in EV secretion following activation of hypoxiaregulated P2RX7 at agonist concentrations that mediate pore formation, suggests a possible underlying mechanism for this effect. This is consistent with recent research suggesting a role of P2RX7 activation in the release of EVs in pathophysiological conditions [65]. P2RX7 activation also led to increased secretion of LOX in the conditioned media, a known mediator of PMN formation in bone.…”

Section: Discussionsupporting

confidence: 93%

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Shah

Tattersall

Hussain

et al. 2022

Preprint

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Breast cancer metastasis to bone is a major contributor to morbidity and mortality in patients and remains an unmet clinical need. Purinergic signalling via the P2X7 receptor (P2RX7) in the primary tumour microenvironment is associated with progression of several cancers. It has also now become evident that intra-tumoural hypoxia facilitates cancer metastasis and reduces patient survival. In this study, we present data suggesting that hypoxia regulates the expression of P2RX7 in the primary tumour microenvironment; and importantly, inhibition with a selective antagonist (10mg/kg A740003) increased cancer cell death via apoptosis in a E0771/C57BL-6J syngeneic murine model. Furthermore, micro-computed tomography demonstrated reduced number of osteolytic lesions and lesion area following P2RX7 inhibition in absence of overt metastases by decreasing osteoclast numbers. We also demonstrate that activation of P2RX7 plays a role in the secretion of extracellular vesicles (EVs) from breast cancer cells. Mass-spectrometric analyses showed a distinct protein signature for EVs derived from hypoxic compared with normoxic cancer cells which elicit specific responses in bone cells that are associated with pre-metastatic niche formation. Thus, inhibiting P2RX7 provides a novel opportunity to preferentially target the hypoxic breast cancer cells preventing tumour progression and subsequent metastasis to bone

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Section: Discussionsupporting

confidence: 93%

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Shah

Tattersall

Hussain

et al. 2022

Preprint

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“…Astrocyte‐derived EVs signal to neurons via multiple mechanisms, including transfer of RNA and protein cargoes and activation of signalling events at the neuronal surface, influencing synaptic activity at both pre‐ and post‐synaptic sites (Antonucci et al., 2012; Prada et al., 2018). In addition, a role for EVs released by glial cells, especially microglia, upon ATP activation is emerging in brain diseases (Lombardi et al., 2021), such as traumatic brain injury (Liu et al., 2017) and tauopathy, where ATP‐induced EVs have been implicated in the spreading of tau protein (Ruan et al., 2020). However, how large glial EVs released upon ATP stimulation move in the extracellular space to reach target neurons and whether large EVs interact with neurons at preferential sites to influence synaptic transmission is unknown.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes‐derived extracellular vesicles in motion at the neuron surface: Involvement of the prion protein

D’Arrigo

Gabrielli

Scaroni

et al. 2021

J of Extracellular Vesicle

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Astrocytes-derived extracellular vesicles (EVs) are key players in glia-neuron communication. However, whether EVs interact with neurons at preferential sites and how EVs reach these sites on neurons remains elusive. Using optical manipulation to study single EV-neuron dynamics, we here show that large EVs scan the neuron surface and use neuronal processes as highways to move extracellularly. Large EV motion on neurites is driven by the binding of EV to a surface receptor that slides on neuronal membrane, thanks to actin cytoskeleton rearrangements. The use of prion protein (PrP)-coated synthetic beads and PrP knock out EVs/neurons points at vesicular PrP and its receptor(s) on neurons in the control of EV motion. Surprisingly, a fraction of large EVs contains actin filaments and has an independent capacity to move in an actin-mediated way, through intermittent contacts with the plasma membrane. Our results unveil, for the first time, a dual mechanism exploited by astrocytic large EVs to passively/actively reach target sites on neurons moving on the neuron surface. K E Y WO R D Sastrocytes, cytoskeleton, extracellular vesicles, neurons, optical tweezers, prion protein, PrP knock-out  INTRODUCTIONExtracellular vesicles (EVs) are circular membrane fragments released by all cells which function as intercellular signalling vehicles. EVs influence the behaviour of target cells in multiple ways, including the transfer of bioactive cargoes and the activation of signalling events at the cell surface (Holm et al., 2018). In addition, EVs possess enzymatic activity and are capable of modifying

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“…Finally, emerging evidence indicates that the activation of microglia may be associated also to release of extracellular vesicles (EVs) from the cell plasma membrane into the pericellular space where they can function as cargo for delivering cellular components to other cells [74,75]. The classification of the vesicle subtypes is ongoing and includes apoptotic bodies (800-5000 nm in diameter), microparticles/microvesicles (MPs/MVs) (100-1000 nm), and exosomes (40-120 nm) [76].…”

Section: Microgliamentioning

confidence: 99%

“…In CNS, the main MVs studied are released by microglia and astrocytes upon ATP activation of P2X7 receptor [74] that is highly expressed on inflammatory cells [95]. In microglial cells, the ATP receptor P2X7 is located in raft domains [96].…”

Section: Nm II In Microglia Morphology and Polarizationmentioning

confidence: 99%

Functional Role of Non-Muscle Myosin II in Microglia: An Updated Review

Porro

Pennella

Panaro

et al. 2021

IJMS

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Myosins are a remarkable superfamily of actin-based motor proteins that use the energy derived from ATP hydrolysis to translocate actin filaments and to produce force. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Several classes of the myosin superfamily are expressed in the nervous system; among them, non-muscle myosin II (NM II) is expressed in both neurons and non-neuronal brain cells, such as astrocytes, oligodendrocytes, endothelial cells, and microglia. In the nervous system, NM II modulates a variety of functions, such as vesicle transport, phagocytosis, cell migration, cell adhesion and morphology, secretion, transcription, and cytokinesis, as well as playing key roles during brain development, inflammation, repair, and myelination functions. In this review, we will provide a brief overview of recent emerging roles of NM II in resting and activated microglia cells, the principal regulators of immune processes in the central nervous system (CNS) in both physiological and pathological conditions. When stimulated, microglial cells react and produce a number of mediators, such as pro-inflammatory cytokines, free radicals, and nitric oxide, that enhance inflammation and contribute to neurodegenerative diseases. Inhibition of NM II could be a new therapeutic target to treat or to prevent CNS diseases.

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Role of ATP in Extracellular Vesicle Biogenesis and Dynamics

Cited by 39 publications

References 90 publications

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Astrocytes‐derived extracellular vesicles in motion at the neuron surface: Involvement of the prion protein

Functional Role of Non-Muscle Myosin II in Microglia: An Updated Review

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