Thematic Review Series: Exosomes and Microvesicles: Lipids as Key Components of their Biogenesis and Functions, Cholesterol and the journey of extracellular vesicles

Pfrieger, Frank W.; Vitale, Nicolas

doi:10.1194/jlr.r084210

Cited by 106 publications

(57 citation statements)

References 90 publications

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“…Indeed, we observed membrane vesiculation events by SXT in direct support of such a mechanism (Fig. 8) 48 .…”

Section: Discussionsupporting

confidence: 66%

“…Another possibility is the exo-vesiculation of the PM followed by release of PM derived vesiclesalso called ectosomes -into the medium. Shedding of microvesicles from the PM has been proposed to be a potential mechanism by which cells communicate, and such vesicles were found to be enriched in cholesterol 48,49 . However, micro-vesicles are very small and unless enriched by a suitably fluorescent marker, hard to detect by fluorescence microscopy.…”

Section: Direct Observation Of Vesicle Shedding At the Pm By Soft X-rmentioning

confidence: 99%

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Analysis of cholesterol export from endo-lysosomes by Niemann Pick C2 protein using combined fluorescence and X-ray microscopy

Dupont

Mlv

et al. 2018

Preprint

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The Niemann-Pick C2 protein (NPC2) is a sterol transfer protein in late endosomes and lysosomes (LE/LYSs). How its capacity to transport cholesterol between membranes is linked to endolysosomal membrane trafficking is not known. Using quantitative fluorescence imaging combined with soft X-ray tomography (SXT); we show that NPC2 mediated sterol efflux is accompanied by large changes in distribution, size and ultrastructure of endocytic organelles. We observed clearance of intra-luminal lipid deposits, a decrease in number of autophagosomes, formation of membrane contact sites (MCSs) to the endoplasmic reticulum and extensive tubulation of LE/LYSs in threedimensional SXT reconstructions of NPC2 treated human fibroblasts. The cells could recycle the cholesterol analog dehydroergosterol (DHE) from LE/LYSs slowly also in the absence of NPC2 protein but internalized NPC2 synchronized and accelerated this process significantly. Most fluorescent NPC2 was retained in LE/LYSs while DHE was selectively removed from these organelles, at least partially by non-vesicular exchange with other membranes. During sterol efflux LE/LYSs were reallocated to the cell periphery, where they could fuse with newly formed endosomes. Surface shedding of micro-vesicles was found, suggesting a pathway for cellular sterol release. We conclude that NPC2 mediated sterol efflux from LE/LYSs controls membrane traffic through the endo-lysosomal pathway.

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“…Indeed, we observed membrane vesiculation events by SXT in direct support of such a mechanism (Fig. 8) 48 .…”

Section: Discussionsupporting

confidence: 66%

Section: Direct Observation Of Vesicle Shedding At the Pm By Soft X-rmentioning

confidence: 99%

Analysis of cholesterol export from endo-lysosomes by Niemann Pick C2 protein using combined fluorescence and X-ray microscopy

Dupont

Mlv

et al. 2018

Preprint

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“…High cholesterol levels increase Aβ in cellular and animal models of AD, and the chemical that inhibits cholesterol synthesis reduces Aβ in this model [37][38][39][40][41]. Moreover, it has been reported that small EVs contain significantly higher cholesterol than do large EVs [38,39]. Therefore, AD brain cells that accumulate high cholesterol might secrete smaller EVs than controls.…”

Section: Discussionmentioning

confidence: 99%

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

Muraoka¹,

DeLeo²,

Sethi

et al. 2019

Preprint

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AbstractIntroductionExtracellular vesicles (EVs) from human Alzheimer’s disease (AD) biospecimens contain amyloid-β peptide (Aβ) and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined.MethodsEVs were isolated from the cortical grey matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning.ResultsLevels of pS396 tau and Aβ were significantly elevated in AD EVs. High levels of neuron- and glia- specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy.DiscussionIn addition to Aβ and tau, ANXA5, VGF, GPM6A and ACTZ are new signature proteins in AD EVs.

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“…In addition to the role of exosomes in tumour progression, altered extracellular vesicle secretion is also linked to several cholesterol-related diseases 66,67 . This attracts particular attention in relation to atherosclerosis, where exosomes may be involved in monocyte and macrophage cholesterol metabolism, endothelial cell and platelet activation, and smooth muscle proliferation.…”

Section: Discussionmentioning

confidence: 99%

ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Albacete-Albacete

Navarro-Lérida

López

et al. 2018

Preprint

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The composition and physical properties of the extracellular matrix (ECM) critically influence tumour cell behaviour, and ECM deposition and remodelling by stromal fibroblast populations is therefore pivotal for tumour progression. The molecular mechanisms by which stromal and tumour cell populations regulate ECM layering are poorly understood. Tumour-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles secreted by most cell types and generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1), an essential regulator of stromal remodelling and tumour cell fate, plays a central role in modulating both exosome biogenesis and exosomal protein cargo sorting through cholesterol-dependent mechanisms. Quantitative proteomics profiling revealed that a major share of Cav1-dependent exosomal cargoes are compsed of ECM proteins, one of the most important components being tenascin-C (TnC). Comparative functional assays demonstrated that Cav1 is required for fibroblast-derived exosomes to depose ECM and promote tumour cell invasiveness. Exosomes purified from Cav1WT cells, but not those from Cav1-null cells, were able to nucleate distant stromal niches in different organs in vivo. These findings suggest a key role for Cav1 as a cholesterol rheostat in MVBs, and seems to determine ECM deposition by eliciting ECM component sorting into specific exosome pools. These results, together with previous work, support a model in which Cav1 is a central regulatory hub for tumour-stroma interactions through a novel exosome-dependent ECM deposition mechanism.

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Thematic Review Series: Exosomes and Microvesicles: Lipids as Key Components of their Biogenesis and Functions, Cholesterol and the journey of extracellular vesicles

Cited by 106 publications

References 90 publications

Analysis of cholesterol export from endo-lysosomes by Niemann Pick C2 protein using combined fluorescence and X-ray microscopy

Analysis of cholesterol export from endo-lysosomes by Niemann Pick C2 protein using combined fluorescence and X-ray microscopy

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

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