The human urinary exosome as a potential metabolic effector cargo

Bruschi, Maurizio; Ravera, Silvia; Santucci, Laura; Candiano, Giovanni; Bartolucci, Martina; Calzia, Daniela; Lavarello, Chiara; Inglese, Elvira; Petretto, Andrea; Ghiggeri, Gian Marco; Panfoli, Isabella

doi:10.1586/14789450.2015.1055324

Cited by 41 publications

(41 citation statements)

References 48 publications

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“…Interestingly there was recently published a paper comparing the urinary, non-urinary and urinary exosome proteomes based on GO annotation. The conclusion of the study was that metabolic proteins are particularly represented in urinary exosomes compared to exosome from other body fluids or compared to the proteome of total urine52. The result of this GO-study is in accordance to our findings: 26 proteins were given catalytic molecular functions (Fig.…”

Section: Resultssupporting

confidence: 87%

“…That enzymes that normally exhibit narrow pH ranges functioning inside the acidic lysosomes are found on the outer surface of urinary exosomes in much less acidic fluid is more convincing explained by that these metabolic enzymes are being wasted out of the organism bound to exosomes. This is contrast to the theory suggested by Bruchi et al that the biological function of metabolic enzymes enriched in urinary exosome is that aerobic energy are important for the lifetime of exosomes and/or their functioning as metabolic effectors52.…”

Section: Resultscontrasting

confidence: 86%

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Isolation and mass spectrometry analysis of urinary extraexosomal proteins

Hildonen

Skarpen

Halvorsen

et al. 2016

Sci Rep

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The aim of the present study was to develop a LC-MS/MS-based proteomic analysis method of urinary exosomal proteins that has the potential to discover disease biomarkers. In short, urinary exosomes from healthy subjects were isolated by immunocapture on magnetic beads, detected by immunofluorescence and TEM, trypsin digested directly on the beads for an accelerated time with no addition of detergents before performing an LC-MS analysis of the trypsinate. To our knowledge, this is the first proteomic analysis of proteins displayed on the outer surface of exosomes. The outer exosome proteome may contain proteins that are of higher biomarker value compared to soluble cargo protein as the proteins projecting into the extracellular milieu might be more directly involved in physiological functions of exosomes. The proteomic analysis identified 49 proteins that were considered significant; the majority is involved in carbohydrate and lipid metabolism or in immune responses. Thirty of the proteins are linked to diseases. The developed proteomic method exploiting urinary exosomes might be of great value in search for diagnostic or prognostic biomarkers of especially metabolic and immune-related diseases.

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Section: Resultssupporting

confidence: 87%

Section: Resultscontrasting

confidence: 86%

Isolation and mass spectrometry analysis of urinary extraexosomal proteins

Hildonen

Skarpen

Halvorsen

et al. 2016

Sci Rep

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“…Various protein compendia of urinary exosomes have been reported35192223242526, but the identification of their miRNA content has been limited to one sequence based study10, and three studies utilising RT-qPCR or microarray approaches that restrict the study to a specific set of known miRNAs71527. The lack of efficient methods to isolate small RNAs from vesicles has been a constraint to miRNA profiling, and there is no consensus regarding the optimal method for isolation of exosomes.…”

mentioning

confidence: 99%

Urinary Exosomes Contain MicroRNAs Capable of Paracrine Modulation of Tubular Transporters in Kidney

Gracia

Wang

et al. 2017

Sci Rep

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Exosomes derived from all nephron segments are present in human urine, where their functionality is incompletely understood. Most studies have focused on biomarker discovery rather than exosome function. Through sequencing we identified the miRNA repertoire of urinary exosomes from healthy volunteers; 276 mature miRNAs and 345 pre-miRNAs were identified (43%/7% of reads). Among the most abundant were members of the miR-10, miR-30 and let-7 families. Targets for the identified miRNAs were predicted using five different databases; genes encoding membrane transporters and their regulators were enriched, highlighting the possibility that these miRNAs could modulate key renal tubular functions in a paracrine manner. As proof of concept, cultured renal epithelial cells were exposed to urinary exosomes and cellular exosomal uptake was confirmed; thereafter, reduced levels of the potassium channel ROMK and kinases SGK1 and WNK1 were observed in a human collecting duct cell line, while SPAK was unaltered. In proximal tubular cells, mRNA levels of the amino acid transporter gene SLC38A2 were diminished and reflected in a significant decrement of its encoded protein SNAT2. Protein levels of the kinase SGK1 did not change. Thus we demonstrated a novel potential function for miRNA in urinary exosomes.Urinary exosomes are lipid membrane-bound nanovesicles released from intracellular multivesicular bodies (MVBs) 1,2 and derived from all cells in the urinary tract [3][4][5] . During the inward budding of endosomes that give origin to exosomes, proteins 2 , mRNAs 6 , microRNAs (miRNAs) 7 , noncoding RNA (ncRNA) 8 , transcription factors 9 and other biomolecules present in the cytosol can be incorporated. The lipid bi-layer of these nanovesicles provides the cargo with stable storage conditions and protects it from degradation by extracellular proteases and ribonucleases 10. Studies in other tissues have shown that once exosomes and other microvesicles are released into the extracellular environment, interactions with cells can occur by direct ligand-receptor signalling, by exosomal fusion to the target cell membrane and discharge of exosomal content directly into the cytoplasm, or via phagocytosis/macropinocytosis 11,12 . Exosomes are known to deliver biologic cargo not only to neighbouring cells but also long distance 13 . The majority of studies concerning urinary exosomes have focused on their potential as biomarkers of disease pathology and progression, including prostate and bladder cancers [14][15][16][17] , but their functional significance is now being addressed. Inter-cellular signalling by exosomes in cultured murine renal epithelial cells was demonstrated for the first time by Street et al. 18 , who suggested that collecting duct cell-derived exosomes can transfer the ability to express AQP2. Our previous studies revealed that urinary exosomes inhibit bacterial growth of both commensal and uropathogenic E. coli by inducing bacterial lysis 19 . Bruschi and colleagues demonstrated that urinary exosomes can consume ...

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“…All exosomes contain membrane transport and fusion proteins and are believed to shuttle selected miRNAs (8), which can also permit their identification. Exosomes are also considered to be biomarkers in different cellular states (9).…”

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confidence: 99%

Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants

et al. 2015

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Exosomes are secreted nanovesicles that are able to transfer RNA and proteins to target cells. The emerging role of mesenchymal stem cell (MSC) exosomes as promoters of aerobic ATP synthesis restoration in damaged cells, prompted us to assess whether they contain an extramitochondrial aerobic respiration capacity. Exosomes were isolated from culture medium of human MSCs from umbilical cord of ≥37-wk-old newborns or between 28- to 30-wk-old newborns (i.e.,term or preterm infants). Characterization of samples was conducted by cytofluorometry. Oxidative phosphorylation capacity was assessed by Western blot analysis, oximetry, and luminometric and fluorometric analyses. MSC exosomes express functional respiratory complexes I, IV, and V, consuming oxygen. ATP synthesis was only detectable in exosomes from term newborns, suggestive of a specific mechanism that is not completed at an early gestational age. Activities are outward facing and comparable to those detected in mitochondria isolated from term MSCs. MSC exosomes display an unsuspected aerobic respiratory ability independent of whole mitochondria. This may be relevant for their ability to rescue cell bioenergetics. The differential oxidative metabolism of pretermvs.term exosomes sheds new light on the preterm newborn's clinical vulnerability. A reduced ability to repair damaged tissue and an increased capability to cope with anoxic environment for preterm infants can be envisaged.-Panfoli, I., Ravera, S., Podestà, M., Cossu, C., Santucci, L., Bartolucci, M., Bruschi, M., Calzia, D., Sabatini, F., Bruschettini, M., Ramenghi, L. A., Romantsik, O., Marimpietri, D., Pistoia, V., Ghiggeri, G., Frassoni, F., Candiano, G. Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants.

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The human urinary exosome as a potential metabolic effector cargo

Cited by 41 publications

References 48 publications

Isolation and mass spectrometry analysis of urinary extraexosomal proteins

Isolation and mass spectrometry analysis of urinary extraexosomal proteins

Urinary Exosomes Contain MicroRNAs Capable of Paracrine Modulation of Tubular Transporters in Kidney

Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants

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