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Exosomes as they relate to developmental origins of diseases related to…
Exosomes as they relate to developmental origins of diseases related to aging
Developmental Origins
Exposure in utero
Substance
Alcohol
Marijuana
Opioids
Nicotine
Hypertension
Maternal Depression
Maternal Anxiety
Maternal high cholesterol
Maternal Exosomes
Diagnostics: Syncytiotrophoblast EVs in maternal circulation; using synctin-1 protein expression as a marker of EV syncytiotrophoblast origin; (note: preeclampsia n=8 :/) ROC curve indicated 95.2% sensitive and 95.6% specific (note: fit to all training data - no testing data); similar EV quantities & size distribution; but lower levels of EV's expressing synctin-1 (p = 2.8 × 10^−11) in preeclampsia patients
https://www.nature.com/articles/s41598-020-62193-7
Exosomal contents mediating changes:
Maternal preeclampsia EVs impaired angiogenesis by delivering sFlt (soluble fms-like tyrosine kinase)-1 and sEng (soluble endoglin) to human umbilical vein endothelial cells
https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.118.11706
Parental age
Foetal disorders
The ratio of placental-derived to total exosomes was significantly reduced in the FGR (fetal growth restriction) group. These results suggest that placental-derived exosomes may reflect foetal growth status and serve as a potential biomarker for FGR.
Q. Can't fetal growth restriction already be determined by ultrasound? If so, what is the benefit in using the exosome ratio?
The development of precise diagnosis may allow implementation of appropriate intervention, which would be helpful for reducing the harm to both mothers and foetus.
However, there are still several problems that need to be addressed before EVs reach the clinic in human reproduction field: no recognized common methods for the discrimination and quantification of different sub‐populations of EVs; due to the difficulty of imitating long‐term effects in vitro and the lack of suitable cell and animal models, controversial and inconsistent results still exist in different studies.
Moreover, human tissues usually only can be obtained after delivery and cannot accurately reflect the dynamic changes of markers during the whole pregnancy process.
Q. What are the contents of these exosomes that indicate CHD vs non-CHD? Also, can't that be picked up by ultrasound? But, oh! Ultrasound quality depends upon the skill of the technician. Using exosomes as biomarkers reduces risk for human error by using a serological assay.
miRNAs, including miR-34a, miR-142-5p, miR-1275, miR-4666a-3p and miR-3664-3p were found in the peripheral blood of pregnant women carrying a foetus with abnormal heart development compared to women with normal pregnancy.
Through whole-genome and exome sequencing of CHD (congenital heart disease) families or sporadic cases, many genes have been revealed to participate in foetal cardiac development regulatory networks.
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Maternal personality disorders
miR-497 (Schizophrenia) and miR-29c (BPD) are overexpressed in exosomes of the prefrontal cortex of patients with schizophrenia or bipolar disorder
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048814
Exposure in childhood
Stress/Trauma (ACE score)
Being in foster care or other markers of stability during childhood
Exercise/obesity/nutrition as a child
Second hand nicotine
Pollutants
Polybrominated diphenyl ethers (PBDEs) &
bisphenols (A [BPA], Tetrabromobisphenol A [TBBPA], & 2,4,6-Tribromophenol [TBP])
Toxin treated placenta led to supernatant containing exosomes with differential protein expression profiles including specific pollutants caused differential expression of >2000 specific proteins, including alarmin, High Mobility Group Box 1 (HMGB1), MAPK14 (p38 MAPK) and GSK3β. See supplemental tables for more info.
https://www.sciencedirect.com/science/article/pii/S0143400419306800
Diseases related to aging
Neurocognitive Disorders
Alzheimers
Exosomes are involved in carrying pathological misfolded proteins, propagation of B-amyloid protein and hyper-phosphorylated tau proteins
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Amyloid Pathology
Exosomes in the brains of patients with AD possess high quantity of Aβ-oligomers, which act as neuron-neuron transfer vectors. This reinforces the correlation between exosomal neuron-to-neuron transfer of intercellular Aβ peptides and progressive extracellular accumulation of Aβ peptides .
Exosome contents have been proposed to induce neuronal apoptosis in astrocytes exposed to amyloid protein.
Combined detection of CSF Aβ1–42 and p-tau might help assist early diagnosis for AD 10 years prior to clinical onset and differentiate early stage AD from frontotemporal lobar degeneration.
Q. Are these exosomes found in circulated blood? Or in CSF? BOTH
Tau proteins
Blood and CSF samples of AD patients revealed the presence of exosomes associated with phosphorylated tau
Plasma neuronal derived exosomes (NDEs) with p-tau leads to the generation of highly pathogenic tau aggregation
Exosome-mediated trans-synaptic transmission of tau through extracellular space suggests a progressive spreading of tauopathy in AD patient's brain
p-tau can be found in CSF exosomes in the early stage, it is helpful for the early diagnosis of AD. Exosome-mediated secretion of p-tau might play a significant role in the abnormal processing of tau and in the increase of CSF tau during early AD.
Q. Is there any way we can relate these to development? Perhaps through preclinical studies? It would be good for us to come up with a repertoire of exosome related databases for each of these phenotypes.
Abnormally phosphorylated Tau proteins 55,64, and 69 found in cerebral cortex were more severe in prefrontal cortex vs temporal area. p-tau231 and p-tau181 yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau.
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Parkinsons
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α-Syn oligomers
α-Syn oligomers appear in the exosomal sections of neuronal and non-neuronal cells.
α-Syn aggregation could be triggered via the interaction of α-Syn with a lipid membrane: exosomes are known to have natural lipid bilayers. interaction between α-Syn and lipid membrane could influence α-Syn folding and aggregation and subsequently facilitate its toxic, oligomeric, or β-sheet structures formation, giving rise to neurodegeneration.
Some genes (LRRK2, VPS35, and PARK9) related to PD come into effect in the autophagy/lysosome pathway, and these genes participate in the formation and release of exosomes at the same time.
The expression level of PARK9 correlates with the amount of exosomal α-Syn released into the medium, indicating that α-Syn expression levels can be altered by PARK9 via exosome-mediated secretion.
Biomarkers and Therapy
Brain-targeted catalase-loaded exosomes that accumulated in neurons and microglial cells efficiently, reduced the secretion of inflammatory cytokines, and remarkably decreased neuronal death in PD mice
Neurotropic factor-loaded exosomes ameliorated neurodegeneration and neuroinflammation, significantly improving neuronal survival in PD mice
siRNA-loaded exosomes could significantly decrease expression levels of α-Syn mRNA and protein compared with the control
dopamine-loaded exosomes were more effective, and the systemic toxicity was lower than free dopamine in a PD mice model
Catalase mRNA-loaded exosomes effectively attenuated neurotoxicity and neuroinflammation in PD mice.
Q. Were these exosomes delivered IV? or via CSF? Or targeted injection to striatum?
PC12 neuronal cells is a common model for in vitro evaluation of drug neuroprotective effects, and exosomes were added to the cells. For biodistribution of exosomes in mouse brain with inflammation: 21 days later (at the peak of inflammation), mice were intranasally (i.n.) or intravenously (i.v.) injected with fluorescently-labelled exosomes.
6-OHDA-intoxicated mice were i.v. injected with exosomes isolated from GDNF-transfected macrophages (This mechanism may play a significant role in GDNF-mediated protection effects, increasing the blood circulation time, reducing immunogenicity, and facilitation of the protein transfer across the BBB and into target neurons. In addition, the membranotropic properties of GDNF-carrying exosomes may facilitate GDNF binding to GFRα-1 receptors expressed on DA neurons)
Peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA.
Blood exosomes were i.v injected into mice
Subcutaneously implanted cells produced CD63 luciferase labelled exosomes, the presence of the designer exosomes in the bloodstream of treated animals were confirmed used an assay.
Seems like exosomes may be a key way to cross the BBB. That's super significant for drug delivery.
Q. As in, there are more exosomes in a PD patient compared to non-PD patients?
PD; non-demented Parkinson’s disease to DLB (dementia with Lewy bodies), and DLB with Alzheimer’s disease at the most severe end.
Abuse of drugs such as opiates during infection further increases the incidence and progression of
HIV-associated neurodysfunction
, although the mechanism for the synergistic effect remains unknown. A recent study by Hu et al suggested that co-exposure of astrocytes to morphine and HIV Tat protein induces the release of exosomes enriched in miR-29b which can impair neuronal function.
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Q. What else do we know about miR-29b?
miR-29b targeting the 3′-UTR region of the neurotropic gene PDGF-B chain as a highly expressed miRNA in the basal ganglia region of SIV-infected, morphine-dependent macaques.
Increased expression of miR-29b in exosomes released from astrocytes treated with morphine and Tat taken up by the neurons, leading to neuronal death (resulting in concomitant decrease in PDGF-B expression).
MiR-29a and b are highly expressed in the CNS.
In rodents, the expression of miR-29 increases with neuronal development and reaches highest levels in adulthood. Moreover, miR-29 contributes to increased BACE1 and αβ levels in sporadic Alzheimer’s disease.
Inhibiting miR-29b expression in neurons resulted in enhanced neuronal survival in vitro, whereas overexpressing miR-29b mimic suppressed neuronal viability.
miR-29a can specifically target HIV-1 mRNA and represses viral replication by accumulating viral mRNA in P-bodies in human T lymphocytes.
Upregulated expression of miR-29b in HIV/SIV and drug abusers, through repression of PDGF-B, and potentially other target genes such as MCP-1, could lead to deficits in neurocognitive functions as seen in HIV-infected drug abusers.
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EVs
Comprehensive proteomic profiling of plasma-derived Extracellular Vesicles from dementia with Lewy Bodies patients
Proteins and nucleic acids contained in extracellular vesicles (EVs) are considered a feasible source of putative biomarkers for physiological and pathological conditions. Dementia with Lewy bodies (DLB) is the second cause of dementia worldwide, though most cases are missed or misdiagnosed as Alzheimer’s disease (AD) due to the important clinical and pathological overlap between both diseases.
Two proteins, BCHE and GSN, showed a specific expression pattern and characteristic distribution between both groups: AD and DLB. The enzyme butyrylcholinesterase (BCHE) is involved in the metabolism of acetylcholine whose deficit is one of the hallmarks of AD and DLB.
Recently, a lower BCHE activity was measured in plasma of patients suffering from DLB than in plasma of controls or AD patients, which could be in accordance with the reduced expression of BCHE we have found in plasma-EVs by MS/MS.
Moreover, a study on the role of GSN in Lewy body diseases reported the presence of gelsolin together with α-synuclein in Lewy bodies of DLB and PD brains as detected by immunohistochemistry. A clear tendency confirmed the reduced presence of GSN in DLB patients observed by MS/MS. The reduced expression of GSN in EVs was seen in DLB compared to AD suggests that the detection of this protein could be useful as peripheral biomarker.
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Extracellular vesicles, new actors in the search for biomarkers of dementias
EV-miRNAs are considered a promising way for the differential profiling of dementia types in a more accurate way.
EX fractions from AD patients showed a tendency of increased miRNA expression compared to controls (miRNAs miR-9-5p, miR-598 and miR-134). hsa-miR-101- 3p, hsa-miR-20a-5p or hsa-miR-106b-5p, had been previously related to AD pathology, and showed higher expression in patients than in controls.
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Alzheimer’s disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles
Suppression of EV biogenesis has been recently hypothesized as a viable strategy for slowing AD neurodegeneration.
Mixed dementias and all analyzed AD stages could only be identified in brain EV from preclinical AD and the influence of the vascular component in brain EV may decay over the course of AD.
The amyloid cascade seems to not interfere with EV biogenesis, especially throughout the disease course, an abrupt increase in the levels of amyloid precursor protein APP in brain EV during preclinical AD was encountered.
EV loaded with APP show the ability to spread Aβ toxicity cell-to-cell. Circulating neuronal EV contain Aβ1-42 up to 10 years prior to the clinical onset of AD.
Significant co-upregulation of the prion protein PrP and APP in brain EV from subjects with AD compared to age-matched controls was observed. Co-upregulation of both proteins in brain EV is highly active only during the preclinical stage of the disease.
PrP was at its highest level in brain EV during the preclinical stage of the disease. The interaction between APP and PrP in brain cells has been largely described although the purpose of that interaction in brain EV remains unknown.
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Cardiovascular
Exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury
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Peripartum cardiomyopathy
Endothelial exosomes can be taken up by cardiomyocytes, resulting in the elevation of miR-146a levels. The exosome-mediated elevation of miR-146a in cardiomyocytes can down-regulate the expression of Erbb4, Notch1, and Irak1, leading to slowed metabolism and impaired contractile function in cardiomyocytes.
Therapy
Facilitates ischaemic cardiac repair by ameliorating cardiomyocyte apoptosis.
Preserves cardiac function and reduces scar size.
Stimulates neovascularization, restrains inflammation response and preserves cardiac function.
Decreases scarring, attenuates adverse remodelling and improves cardiac function after MI
Double-edge sword
Promotes cardiomyocyte hypertrophy. Induces endothelial cell apoptosis and cardiac dysfunction. Reduces metabolic activity in cardiomyocytes. Inhibits myocardial endothelial cell promotion, migration and tube formation.
Q. Why miR-146a?
PPCM (peripartum cardiomyopathy) is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood.
16K PRL–miR-146a circuit appears to play a major role in the development of PPCM.
miR-146a may serve as a specific biomarker for the diagnosis of PPCM in patients and that miR-146a may represent a novel therapeutic target to treat PPCM.
16K PRL mediates antiangiogenic effects in ECs through miR-146a.
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Diabetic cardiomyopathy
The exosomal miR-320 (transported to endothelial cells) results in decreased levels of IGF-1, Ets2 and Hsp20 and thereby, inhibiting angiogenesis in diabetic hearts.
Q. What else do we know about miR-320 that might help explain this story?
Cardiomyocytes isolated from the type 2 diabetic rats elicited inhibitory effects on angiogenesis through the exosomal transfer of miR-320 into endothelial cells.
Type 2 diabetic GK rat-derived cardiomyocytes secrete miR-320-enriched exosomes, which can be taken up by endothelial cells and inhibit myocardial angiogenesis. Transportation of miR-320 from cardiomyocytes to endothelial cells is dependent on exosomes, indicating their pivotal role in local cell-cell communication.
miR-320 has been predicted to target multiple angiogenesis-related genes, such as Flk-1, VEGF-c, IGF-1, IGF-1R, FGFs, Hsp20 and Ets2.
miR-320 that is transferred from cardiomyocytes into neighboring endothelial cells can be one of the extracellular signaling molecules that can mediate anti-angiogenesis in diabetic hearts. The major limitation of this study is that it wasn’t validated if miR-320- enriched exosomes released from diabetic cardiomyocytes would impair myocardial angiogenesis in vivo.
Such an issue could be addressed using an inducible cardiac-specific overexpression of miR-320 animal model upon diabetic conditions [i.e. streptozotocin (STZ)-induced diabetes]. Also, it would be important to address whether cardiac-specific deletion of miR-320 could improve myocardial angiogenesis in diabetes mellitus.
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link to www.sciencedirect.com
In hypoxic or ischaemic environments, large numbers of exosomes with unique miRNA are released into plasma; thus, exosome levels are elevated in patients with CVDs or AMI
Septic cardiomyopathy
Sepsis can cause higher levels of lipopolysaccharide (LPS) and nitric oxide (NO) in the blood, which stimulate platelets to secret inflammatory exosomes (enriched with NADPH, NOS, PGI, ICAM-1 and less miR-223) which activate ROS/RNS signaling pathways, increase NO production and activate caspase-3 in both endothelial cells and cardiomyocytes, resulting in cell apoptosis and dysfunction and consequently, cardiomyopathy.
Is there any data related to increase risk of sepsis in FASDs population? Or other developmental exposed populations?
No
Cardiomyocyte hypertrophy
In-vivo studies show that exosomal miR-21* plays a critical role in regulation of the cardiac fibroblast secretome and in determining a hypertrophic response.
Q. Why miR-21?
To analyze the miRNA content of fibroblast-derived exosomes, a miRNA profiling assay was done.
25.5% of fibroblast derived exosome-enriched miRNAs were so called “star” miRNAs, representing the passenger (star) strand that often is degraded within a cell.
miRNA profiling in exosomes identified miR-21
to be enriched in fibroblast-derived exosomes, suggesting that miR-21
might be transported out of the cardiac fibroblast via exosomal transfer.
Fibroblast-derived miR-21
is transported to cardiomyocytes, leading to cellular hypertrophy. In-vivo evidence: miR-21
was significantly increased in pericardial fluid of mice with cardiac hypertrophy compared with that in sham-operated mice.
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EVs in Cardiovascular homeostasis and disease
Endothelial-derived EVs loaded with microRNA-126 prevents SMC proliferation, migration, and neointima formation in a mouse model of vascular injury.
Endothelial cell-derived EVs containing microRNA-126 can affect tissue homeostasis through both local regulation of vascular SMC phenotype and distal recruitment of leukocytes.
EVs can serve as a mechanism for delivery of ECM and mineral components to help the vascular SMCs respond to lost extracellular homeostasis.
SMCs exposed to atherogenic lipoproteins release EVs with significantly altered microRNA profiles, including a decrease in microRNA-24-3p and -130a-3p. microRNAs exhibit decreased expression in circulating EVs from individuals with familial hypercholesterolemia. In addition to their diagnostic potential, however, recent studies have shown a tremendous capacity for EVs to serve as therapeutic agents and restore tissue homeostasis.
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Extracellular vesicles and cardiovascular disease therapy
miR-210 was shown to inhibit apoptosis in cardiomyocytes.
miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells.
The cardioprotective effect of ESC-derived EV after AMI is specifically tied to miR-294 delivery to CPC promoting increased survival, cell cycle progression, and proliferation.
miR-126 has been previously identified as a critical regulator of angiogenesis and vascular integrity and shown to be also enriched in EV derived from endothelial cells
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EVs in CVDs
Numerous studies have shown that EV, mainly microparticles, interact with cells from the vascular wall, mainly endothelial cells and smooth muscle cells.
EVs induce endothelial dysfunction by (i) decreasing NO signaling by reducing the activity of endothelial NO synthase via an increased phosphorylation of the enzyme at its inhibitory site (Ser495) or by decreasing NO bioavailability, (ii) decreasing cyclic GMP production, (iii) increasing protein nitration on endothelial cells and (iv) enhancing plasmatic oxidative stress markers.
EV also participate in atherosclerosis. Indeed, EV secreted by endothelial cells stimulated by high shear-stress are enriched in miR-143/145. Once transferred to smooth muscle cells, these vesicles reduce the expression of miR-143/145 targets such as ELK1 and CAMK2d, two central regulators of smooth muscle cell phenotype, and promote de-differentiation and repress proliferation of smooth muscle cells, an event associated with atherosclerosis progression.
Injured myocardium can generate EV enriched with miR-1 and miR-133a reported to induce cardiac hypertrophy by targeting mRNAs associated with myotrophin and the TGF- signaling pathway. Since this type of EV is significantly increased in patients with acute myocardial infarction and angina pectoris, they may be used as a potential marker for cardiomyocyte death.
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Immune-related
Rheumatoid Arthritis
RA is associated with synovial hyperplasia and chronic inflammation that leads to joint destruction.
Exosomes produced by synovial fibroblasts (in RA, synovial hyperplasia is observed) obtained from patients with RA contain a membrane form of TNF-α known as APO2L/TRAIL that; by inducing AKT and NF-κB; which renders these cells resistant to apoptosis. But, APO2L/TRAIL associated with exosomes in synovial fibroblasts [is this from synovial fluid, or are fibroblasts taking up the exosomes?] from RA patients appears to be low compared to that found in the synovial fibroblast of control patients.
Synovial exosomes contain citrullinated proteins (these proteins are involved in the development of RA) and the expression of these proteins plays an important role in the induction and distribution of citrullinated proteins and presumably in the activation of those subsets of T cells that are specific to citrullinated proteins. This plays a role in the perpetuation of synovial inflammation in
RA.
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Q1. What other effects do APO2/TRAIL, AKT, NFkB, citrullinated proteins have on cells of the synovial membrane? What about other than fibroblasts? What other cell types are there?
Intra-articular injection of recombinant TRAIL induces synovial apoptosis and reduces inflammation in a rabbit knee model of arthritis: shows extensive acellular debris and large fibrous regions devoid of intact cells.
Has therapeutic benefits for RA treatment. It appears as if the apoptotic effect of the over-expression of TRAIL on the synovial fibroblasts from RA patients is mediated predominantly by TRAIL R1 as its expression varied from patient to patient.
TRAIL is a potent inhibitor of autoimmune arthritis unlike TNF which in fact promotes inflammation.
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PI3K/Akt inhibitor LY294002 decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis. Synovial inflammation is increasingly recognized as contributing to the pathology during progression of osteoarthritis.
PI3K/Akt pathway can be activated by several cytokines such as TNF-α in RA synoviocytes.
TNF-α induces the increase of Cadherin-11 expression via PI3K/Akt pathway in OA FLS and thus plays an important role in synovial inflammation.
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In the animal arthritis models, expression of activated NF-κB p65 was found in the synovial lining layer and surrounding the blood vessels in the inflamed synovium.
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These exosomes are associated with citrullinated proteins, including fibrin‐derived molecules and Spα.
Citrullinated proteins complexed to exosomes with fibronectin may enhance T cell immunogenicity. Their presence alone cannot be held responsible for the generation of ACPAs (autoantibodies to citrullinated proteins) that are highly specific for RA.
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Q2. What stimulates these upregulated proteins to be upregulated in the first place?
Clarification of the mechanism underlying the upregulation of PI3K/Akt induced by TNF-α should be examined with promising results in the field of potential alternative treatments of OA.
The extracellular signals that activate NF-κB in development have not been fully elucidated.
Citrullination of proteins is not observed exclusively in RA; it is also observed in other inflammatory conditions. Their presence is not specific to rheumatoid synovial tissue.
Q3. What about in preclinical studies? Are the any exosome databases or papers that exist related to animal models of RA? These might help show developmental origins of it as well... ?
EVs in Rheumatoid Arthritis
Antigen presentation and immune complex formation
: Proteins such as DEK, vimentin, fibrin, fibronectin, fibrinogen, and AIM are present in the membrane. These become citrullinated and are thought to activate the innate and adaptive immune system, resulting in inflammation.
Inflammation
:EVs stimulate production of TNF-α, IL-6, IL-8, and mPGES-1, further increasing inflammation. Platelet-derived EVs are found in patients with RA and increase inflammation in an IL-1 receptor-mediated mechanism. Presence of EV-based immune complexes causes increased inflammation. EVs can activate TLR4, which triggers anti-inflammatory genes.
Destruction of ECM
: Carry catabolic proteases such as MMPs, ADAMTS-5, Hexosaminidase D, and B-glucuronidase which causes the breakdown of ECM, resulting in the destruction of cartilage and more inflammation.
Biomarker
: The presence of citrullinated proteins in EV membrane is a potential biomarker that is specific to RA
Delivery of miRNA
: Dendritic cells are known to secrete EVs with increased levels of miR-155 and miR-146a in response to inflammation
Therapy
: EVs derived from IL-10-treated dendritic cells have shown anti-inflammatory properties in patients with RA. EVs have also been created that can target the synovial membrane specifically.
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EVs in Osteoarthritis
Communication between Fibroblast like synoviocytes(FLS) and chondrocytes:
EVs isolated from chondrocytes treated with inflammatory cytokines are known to increase inflammatory cytokine production and MMP-13 production by FLS.
Biomarker
: Differences in content of synovial fluid and plasma EVs can serve as a biomarker for disease. miR-200c is elevated compared with non-OA patients.
In females, miR-16-2-3p was up-regulated and miR-26a-5p, miR-146a-5p and miR-6821-5p were down-regulated. In synovial fluid from male OA patients miR-6878-3p was down-regulated and miR-210-5p was up-regulated.
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Therapy
: Deliver miRNA to cells altering response to inflammation. Potential to target the reduction of MMP-13 production using miRNA.
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Cancer
Cancer exosomes may serve as a liquid biopsy to aid in the diagnosis of malignancies, including prostate, pancreas, breast, and ovarian cancers; glioblastoma; and melanoma
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DNA and proteins in cancer exosomes
DNA in exosomes may provide information about cancer-specific mutations. Enriched and specific miRs in exosomes may also inform diagnosis and serve to monitor the progression of cancer. For eg, exosomal miR-21 is increased in the serum of patients with esophageal squamous cell carcinoma and correlates with advanced disease stage.
Intercellular transfer of oncoproteins by exosomes may play a role in facilitating tumorigenesis. For eg, in stage 3 and stage 4 melanoma patients, circulating exosome–associated MET (also known as a hepatocyte growth factor receptor) and phosphorylated MET (Tyr1349) are increased compared with healthy controls
Q. Why miR-21?
Previous studies showed a possibility that anti-microRNA-21 may have potential therapeutic value. For example, it was shown that high microRNA-21 expression was associated with poor survival for those who received adjuvant chemotherapy in patients with stage II or III colon cancer. In addition, it was shown that inhibition of microRNA-21 increased sensitivity to anticancer drugs in cancer cell lines. These findings may show that chemotherapy combined with microRNA-21 suppression is more effective than chemotherapy alone. Therefore, we suggest that microRNA-21 may serve as potential target for cancer therapy in patients with not only esophageal squamous cell carcinoma but also various types of cancer.
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Tumor immunity
The immunological activities of exosomes in tumors are likely complex and dynamic, ranging from modulation of tumor antigen presentation to polarization of tumor immunity.
Cancer cell–derived exosomes can impact T cell biology by inducing T cell apoptosis.
Fas ligand (FasL) on cancer cell–derived exosomes induces apoptosis of Fas+ T cells
This is wild! (esp last point). I would love it if we could find a connection between the FasL and developmental conditions.
Expression of Fas ligand (FasL) and Fas receptor (FasR) as the proteins of the post-apoptotic pathway in colorectal carcinoma was studied. These proteins could become good therapeutic targets for colorectal carcinoma since their expression differs distinctly between normal intestinal epithelium and cancer cells.
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The interaction of Fas and FasL may constitute a common pathogenic mechanism mediating target destruction in organ-specific autoimmunity and some autoimmune diseases.Expression of apoptosis-related protein (Fas, FasL, and Bcl-2) in the pathogenesis of autoimmune thyroid disorders (ATDs) such as Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). The expression of Fas, FasL in Hashimoto’s thyroiditis and Graves’ disease were almost same. FasL strong expression in HT may induce apoptosis. These results provided evidence for expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disease.
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Disregulated apoptosis has been implicated in several neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Recent reports have suggested that the key apoptosis regulator Fas ligand (FasL) may participate in both neuronal and immune cell apoptosis in Alzheimer’s disease. Firstly, the higher amount of FasL and the paucity of T cell infiltration around plaques was seen in AD. Secondly, a negative feedback loop may be activated to halt production of more Aβ, which would likely involve altering metalloproteinase expression and activities. Both of these responses would have consequences for FasL expression and regulation. FasL plays an even more complicated role in balancing the beneficial and detrimental effects of immune access to the CNS.
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Tumor angiogenesis
Angiogenic programs launched by hypoxia-induced cell signaling in cancer cells can be influenced by exosomes. The impact of tumor-derived exosomes on vascular remodeling may not only affect tumor growth, but metastasis as well.
Therapy
Efforts to suppress horizontal transfer of miRs from cancer cells to ECs via exosomes attenuates angiogenesis and metastasis. Tumor stroma–derived exosomes have also been implicated in cancer chemoresistance, supporting the notion that targeting specific functions of exosomes could enhance response to therapies.
Double-edge sword
Exosomes may also negatively impact chemotherapy treatment by shuttling out chemotherapeutic agents from target cancer cells.
This could easily be expanded for each phenotype/disease
I want this aspect to be explored more. Seems like there is much more to this part of the story. HIF1a, HIF1b, ARNT....
Cancer-associated fibroblasts
Cancer cell–derived exosomes induce normal lung fibroblast activation (myofibroblast differentiation) in vitro and promote acquisition of myofibroblast-like features in mesenchymal stem cells derived from adipose tissue.
Tumorigenesis
Cancer exosome miR may also contribute to tumorigenesis, and cancer exosomes can mediate cell-independent miR biogenesis, a property not associated with normal exosomes. Cancer exosomes with RNA-induced silencing complex–associated (RISC-associated) miRs induce tumor formation by nontumorigenic mouse mammary cells (MCF10A cells).
I want to expand this
ECM remodeling and tumor metastasis
Exosomes contain active proteases capable of ECM degradation, and they contribute to ECM remodeling by selectively and directly binding to the ECM-binding motif present on exosomal surface adhesion proteins
In tumors, the local impact of exosome-mediated cell signaling has generally been reported to promote invasive features of cancer cells associated with metastasis.
EVs
EVs are involved in every step of cancer development:
During cancer initiation, normal cells (epithelial cells) attempt to prevent the outgrowth of precancerous cells (or cancer cells) by secreting antiproliferative miRNAs through EVs; however, the cancer cells can circumvent this inhibitory machinery, finally resulting in tumor expansion.
Cancer cells utilize EVs to mediate horizontal transfer of genes that promote proliferation to cancer cells that do not harbor those genes.
Cancer cell–derived EVs promote cancer malignancy (i.e., the induction of inflammation by infiltrating neutrophils).
Additionally, cancer cell–derived EVs activate fibroblasts, leading to extracellular matrix degradation and the induction of cancer-promoting cytokines.
When the tumor microenvironment is hypoxic, cancer cells secrete angiogenesis-inducing EVs that help to overcome oxygen and nutrition deficiency by activating endothelial cells to stimulate vascularization contributing to further cancer development, such as metastasis.
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The roles of cancer cell–derived EVs and their development
EVs derived from cancer cells infiltrate BM cells leading to the formation of a premetastatic niche.
Additionally, cancer cell–derived EVs directly alter the metastatic site to induce angiogenesis.
Transfer of EV-associated miRNAs from BM mesenchymal stem cells regulates breast cancer cell dormancy in a metastatic niche.
Brain metastasis is mediated by EVs triggers the destruction of the BBB
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EVs in Stroke
Stroke
(1) MSCs release EVs in response to the ischemic brain microenvironment
(2) intravenously injected MSC-EVs, as well as MSCs, promoted neurogenesis and angiogenesis in a dose-dependent manner to support recovery after stroke
(3) MSC-EVs can effectively migrate into the infarcted brain, avoiding cell trapping in the lung and liver
(4) miRNAs such as miR-184 and miR-210 contained in MSC-EVs may be associated with the therapeutic efficacy for neurogenesis and angiogenesis, respectively.
This data also supported the important role of miRNAs such as miR-184 and miR-210 largely contained in MSC-EVs for neurogenesis and angiogenesis, respectively. Previous reports demonstrated that miR-184 promoted the proliferation of NSCs and inhibited differentiation by repressing Numblike (Numbl), a known regulator of brain development, by binding to the 3′-UTR of Numbl mRNA and affecting its translation.
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Although the mechanisms by which MSCs act are still elusive, recent evidence has suggested that EVs might be responsible for MSC-induced effects under physiological and pathological conditions. A study has demonstrated that EVs are not inferior to MSCs in a rodent stroke model and EVs induce long-term neuroprotection, promote neuroregeneration and neurological recovery, and modulate peripheral post-stroke immune responses.
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2157-6580.TheBestPapersfromour2016YoungInvestigators)
NSC EV treatment was neuroprotective and led to significant improvements at the tissue and functional levels in stroked pigs. NSC EV treatment eliminated intracranial hemorrhage in ischemic lesions in NSC EV pigs versus control pigs. NSC EV–treated pigs exhibited a significant decrease in cerebral lesion volume and decreased brain swelling relative to control pigs. NSC EVs significantly reduced edema in treated pigs relative to control pigs, NSC EVs preserved white matter integrity with increased corpus callosum.
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MSC-secreted EVs have been demonstrated to promote neural repair and functional recovery in animal models of ischemic stroke. It was indicated that intravenous delivery of exosome-enriched EVs generated from BM-MSCs
significantly improved axonal plasticity and neurite remodeling in the ischemic cortex of middle cerebral artery occlusion (MCAO) rats
.
EVs from MSCs were reported to
modulate signaling pathways to treat ischemic stroke
.
The expression of miRNA-133b in MSC-released exosomes increased when MSCs were cultured with ischemic brain extracts from rats subjected to MCAO. Further research demonstrated that EVs from BM-MSCs were able to transfer miRNA-133b to astrocytes and neurons in the ischemic boundary zone of rats, resulting in promotion of neural plasticity and functional recovery.
EVs may
have immunosuppressive effects on cerebral inflammatory-related diseases
. EVs from BM-derived MSC lineages were able to
modify immune reactions and restore the reshaping ability of the injured brain following focal cerebral ischemia.
Alongside the normalization of B lymphocytes, natural killer cells and T lymphocytes, a deactivation of dendritic cells was observed in the peripheral blood of MSC-EV-treated mice and the suppression of immune responses provided an appropriate extracellular environment for neurovascular remodeling and contributed to the functional recovery following a stroke.
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Has a whole table of EV transcriptomics related to adult diseases
https://www.nature.com/articles/s12276-019-0226-2/tables/1
Paper Organization Thoughts:
A task: Incorporate References into EndNote
A task: Make Excel sheet that organizes contents of exosomes. As in,
Column A would be labeled "association_id";
Column B = "Exosome_Molecule";
Column C = "Associated_Exposure_Disease";
Column D = "up_down_regulated";
Column E = "reference_link"
Column F = "hypothesis_relevance"
Note: There may be more than one line for each molecule. That is ok. Organizing it in this fashion makes it easier to search for associations.
A thought: We have largely considered exosome contents. I wonder if there are other properties we should be considering? Perhaps: Membrane-bound contents v cytosol? or for the contents see if we can take it a step further to hypothesize a reason as to its dysregulation
Journal of Aging and Disease:
Stroke, Alzheimer, Parkinson, Epilepsy, Dementia, Depression, Cardiovascular Disease, Cancer, Arthritis, Cataract, Osteoporosis, Diabetes, Hypertension
Diseases related to aging (contd)
Epilepsy
Epileptogenesis refers to the development and extension of tissue capable of generating spontaneous seizures, resulting in (a) development of an epileptic condition and/or (b) progression of the epilepsy after it is established. Epilepsy is a disease of the brain defined by any of the following conditions: (a) at least two unprovoked (or reflex) seizures occurring >24 h apart, (b) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years, and (c) diagnosis of an epilepsy syndrome
Post traumatic epileptogenesis: Positive enrichment of EV-related genes was also observed in the hippocampus 3 months after amygdala stimulation-induced epilepsy. In 2016, Kim et al. first optimized MSCs to produce anti-inflammatory EVs. They then demonstrated that MSC-EV treatment decreased the level of proinflammatory cytokine IL-1β in mouse brain in a dose-dependent manner post-TBI.
The beneficial effects of EV therapy in epilepsy: MSC-EVs were used to treat pilocarpine-induced SE in mice. Intranasally-administered EVs reached the hippocampus within 6 h following administration. There was a decrease in proinflammatory signals and an increase in anti-inflammatory cytokines within the hippocampus at 24 h post-SE, reduced neuron loss 4d post-SE, promoted normal neurogenesis in the hippocampus, and preserved cognitive functions in the chronic phase.
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EVs in Epilepsy
Approximately 30% of patients with epilepsy have temporal lobe epilepsy (TLE) typified by the progressive development of complex partial seizures, hippocampal neurodegeneration, and comorbidities such as cognitive and mood impairments. Status epilepticus (SE) is a life-threatening medical and neurological emergency that requires prompt diagnosis and treatment, otherwise leading to significant morbidity and mortality. SE is a single epileptic seizure lasting more than five minutes or two or more seizures in five minutes without the person returning to normal between them. It is well known that SE could lead to lasting brain dysfunction through epileptogenic changes, leading to chronic epilepsy.
As biomarkers
In comparison with controls, samples with TLE showed elevated levels of miR-19b-3p, on the other hand, EVs from samples with SE showed elevated levels of miR-21-5p, miR-451a,and downregulation of miR-204-5p: CSF in humans
Mesial TLE with hippocampal sclerosis (mTLE-HS): plasma derived EVs in humans: In EVs from patients with mTLE-HS, elevated expression was seen for miR-3613-5p (~11-fold increase) and miR-6511b (~2-fold increase)
plasma EV miR-8071 (down regulated) was considered as a key diagnostic marker for mTLE-HS because of its 83.3% sensitivity and 96.7% specificity for the disease. Also, miR-8071 was well associated with seizure severity.
In therapy
An episode of status epilepticus causes neurodegeneration as well as acute neuroinflammation. These initial adverse effects progress into chronic neuroinflammation and the occurrence of spontaneous seizures. Therefore, administration of MSC-derived EVs into the brain immediately after SE or after the development of chronic epilepsy is likely to be beneficial for modulating inflammation-related brain impairments, which may include cognitive dysfunction and spontaneous seizures.
Indeed, patients experiencing SE have an increased risk of developing chronic epilepsy and cognitive problems. Intranasal administration of EVs after SE also provided robust neuroprotection, which was evinced through reduced neuronal loss.
Neuroprotective effects may reflect a consequence of strong anti-inflammatory effects of EVs.
Nevertheless, further studies are critical at protracted timepoints after SE to characterize whether the magnitude of antiinflammatory, neuroprotective, neurogenic, cognitive, and memory-protective outcomes facilitated by these EVs are enough to avert the advancement of SE-induced initial precipitating injury into a chronic epileptic state.
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Cataract
Rhegmatogenous retinal detachment (RD) is the most common type of RD and proliferative vitreoretinopathy (PVR) is the most common disease that develops from RD. Retinal cell-type specific EVs can be detected after RD, and EV concentrations are predictive of the RD duration and pro-inflammatory factors known to induce photoreceptor apoptosis, supporting the notion that analysis of vitreal EVs may aid in the prognosis of RD surgery and visual recovery. miR146a and miR26a were upregulated in the vitreous humor of uveal melanoma patients.
In BMSC EV-treated animals, retinal ganglion cell (RGC) survival and axon regeneration increased and RGC axonal loss and RGC dysfunction decreased.
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Osteoporosis
This study used USCs (human urine-derived stem cells) that exhibited MSC-like properties and could be noninvasively harvested from unlimited and easily available human urine as the parent cell source to obtain EVs (USC-EVs) and determined that the systemic injection of USC-EVs effectively inhibited bone loss and increased bone strength in osteoporotic mice due to their dual effects on bone metabolism, which not only enhanced osteoblastic bone formation but also reduced osteoclastic bone resorption.
The anti-osteoporotic properties of USC-EVs were not notably disturbed by the age, gender, or health condition (with or without osteoporosis) of the USC donor, as USC-EVs from a healthy boy, healthy adult man and woman, and postmenopausal osteoporotic woman could induce notable anti-osteoporotic effects.
CTHRC1 was also expressed by USCs; moreover, this protein was enriched in USC-EVs and required for the USC-EV-induced promotion of osteogenesis and inhibition of osteoclast formation. USC-EVs also contained highly abundant OPG protein, which is an evolutionarily conserved secretory glycoprotein that can inhibit osteoclastogenesis by neutralizing RANKL (a key mediator of osteoclast formation and function). Further studies showed that OPG partially mediated the anti-osteoclastic and bone-protective effects of USC-EVs. Our results suggest that USC-EVs deliver functional CTHRC1 and OPG to enhance osteogenesis and suppress osteoclastogenesis, thus enhancing bone mass and strength. Notably, the downregulation of either CTHRC1 or OPG did not entirely block the bone-protective effects of USC-EVs, which suggests that other factors may also be implicated in mediating these processes.
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UCB-EVs ameliorate bone loss in senile osteoporotic mice. UCB-EVs enhance osteoblast activity and decrease osteoclast activity in senile osteoporotic mice. miR-3960 is enriched in UCB-EVs. UCB-EVs promote osteoblast differentiation by transferring miR-3960 and inhibit osteoclast differentiation in vitro.
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Human umbilical cord mesenchymal stromal cell (MSC)-derived extracellular vesicles (hucMSC-EVs) possess considerable therapeutic effects in tissue repair and regeneration. Proteomic analysis showed that the potently pro-osteogenic protein, CLEC11A (C-type lectin domain family 11, member A) was very highly enriched in hucMSC-EVs. In addition, hucMSC-EVs enhanced the shift from adipogenic to osteogenic differentiation of BMSCs via delivering CLEC11A in vitro. Moreover, CLEC11A was required for the inhibitory effects of hucMSC-EVs on osteoclast formation.
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Hypertension
MSC EV were highly effective at both preventing and reversing pulmonary hypertension in the rat Sugen/Hypoxia (Su/Hx) model. MSC-EV are able to return right ventricular systolic pressure (RVSP) to baseline levels even when administered 3 weeks after exposure to Su/Hx at a time when pulmonary hypertension is already established. Further, we found that MSC-EV were also effective at reversing RV (right ventricle) hypertrophy and muscularization of peripheral pulmonary arteries.
Despite the growing body of evidence supporting the efficacy of MSC EV in attenuating pulmonary hypertension, the mechanisms responsible for this effect are unclear. MSC and their EVs have broad immune-modulating effects on multiple inflammatory cells that have been implicated in pulmonary vascular remodeling.
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Several EV derived miRNAs, such as miR-21-5p, let-7c-5p and let-7a-5p, were found to be abnormally expressed in brain microvascular pericytes obtained from spontaneous hypertensive rats, compared with that of normotension Wistar Kyoto rats.
Several EV miRNAs of brain microvascular pericytes were found to be differentially expressed between SHR and WKY rats and may be potential biomarkers or therapeutic targets for hypertension. miR-21, which is well known for its critical roles in the development of hypertension, was found to be upregulated in EVs from brain microvascular pericytes in SHR, compared with that of WKY rats. miR-21 has been identified to perform a positive function in mitochondrial translation, while it has been shown to decrease blood pressure and suppress cardiac hypertrophy in SHR.
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EVs from patients with pulmonary arterial hypertension (PAH) induce transcription and release of VEGF-A, FGF-2, and VEGFR-1 together with an increase in angiogenesis with tube formation of human pulmonary artery endothelial cells, partially modulated by PSGL-1 blockade.
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EVs from MCT (monocrotaline)-injured mice play a pathogenic role in the pulmonary vascular remodelling of MCT-induced PH hypoxia-induced pulmonary hypertension (PH), in part by inducing differentiation of bone marrow cells into EPCs (endothelial progenitor cells) that home to the lung and contribute to pulmonary vascular remodelling. EVs from pulmonary hypertensive mice were also found to have a direct anti-apoptotic effect on PVECs (pulmonary vascular endothelial cells). Incubation of PVECs with MCT-EV reduced the number of apoptotic cells to less than a third of that seen in control cells. Apoptotic-resistant endothelial cells are felt to play an important role in the development of obliterative vascular lesions in PAH and may contribute to the pulmonary vascular remodelling seen in EV-induced PH.
MCT-LEV (lung tissue-derived EV) and PEV (pulmonary arterial hypertension) also showed altered expression of a variety of miRNAs that appear to be involved in pulmonary vascular remodelling. Of the six miRNA species that were found to be greater than two-fold up-regulated in both MCT-LEV and -PEV, two (miR-145, -451) have been found to be increased in hypoxia and MCT models of PH and implicated in its pathogenesis. A third, miR-328, has been shown to suppress the insulin growth factor-1 receptor, ultimately leading to apoptosis of pulmonary arterial smooth muscle cells, but is down-regulated the lungs in hypoxic PH.
The ability of MCT-EV to induce PH in healthy mice strongly implicates a role for EV in the pathogenesis of MCT-induced PH and may represent a potential new target for the development of better biomarkers and therapies for pulmonary hypertensive diseases in human patients.
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Diabetes
In diabetes mellitus, the exosomes cargo may signal to transform a normal phenotype into a diabetic phenotype in endothelial cells. The evidence of EVs as modulators of cell function is increasing; however, it is still unclear whether exosomes or micro vesicles are a trustable and useful marker for the diagnose or early detection of obesity or diabetes mellitus.
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The islet mesenchymal stem–like cells (iMSCs) are located at the periphery of normal islets but permeate into beta cell areas when insulitis occurs. In addition, iMSCs can release highly immunostimulatory exosomes that are able to activate T and B cells to produce numerous cytokines, including interleukin-6 (IL-6), interferonγ (IFN-γ), tumor necrosis factor α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) through a TLR4/MyD88mediated pathway [Exosomes Released by Islet-Derived Mesenchymal Stem Cells Trigger Autoimmune Responses in nonobese diabetic NOD Mice, a mouse model of Wolfram syndrome has also been established. Deletion of the WFS1 gene leads to diabetes as a result of β-cell ER stress and apoptosis.
The inflammatory cytokines are highly irritating to beta cells, which can induce cellular endoplasmic reticulum (ER) stress. Infiltrative T lymphocytes can directly induce beta cells apoptosis by secreting exosomal microRNAs (miR-142-3p, miR-142-5p, miR-155) and increase the production of beta cells chemokines, which can promote the recruitment of immune cells to destroy beta cells.
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Patients with established T1D have higher levels of total circulating EV and endothelial- and platelet-derived EV and have variations in their procoagulant activity indicating the existence of differential EV profiles in T1D. EV miRNA represent a more specific tool for biomarker detection as they are enclosed by lipid membranes, and therefore stable in circulation, whereas circulating miRNA may be subjected to degradation by RNase.
Circulating serum levels of 11 miRNAs are consistently dysregulated in T1D, including miR-21-5p, miR-24-3p, miR-100-5p, miR-146a5p, miR-148a-3p, miR-150-5p, miR-181a-5p, miR-210-5p, miR-342-3p, miR-375, and miR-1275. The Ricordi group recently reported that in long-standing T1D, plasma EV samples showed upregulation of one miRNA (miR-25- 3p), while six others were downregulated (miR-16, miR302d-3p, miR-378e, miR-570–3p, miR-574-5p, miR-579) as compared to controls. Interestingly, high levels of miR25-3p have been shown in new-onset T1D patient samples and its over expression has been shown to inhibit insulin synthesis.
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Adipose tissue macrophages–derived exosomes (ATMEXOs) were found to represent a new mechanism in modulating insulin signaling, the enrichment of miR-155 in obese ATM-EXOs was identified as the cause that induced these disorders
It has been shown that miR-155 can directly inhibit the expression of peroxisome proliferator–activated receptors γ (PPARγ) and its downstream target genes, such as glucose transporter 4 (GLUT4). These genes are related to the differentiation and maturation of adipocytes and insulin-stimulated glucose uptake, respectively, and their repression could directly affect cellular glucose uptake and insulin sensitivity, especially in the liver, adipose tissue, and skeletal muscle.
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Accumulating evidence confirms that EVs are a potential cause in the pathogenesis of T2DM as well as an important factor for inducing diabetic complications. Some EVs can induce insulin resistance via activating inflammation, down-regulating GLUT4, and affecting insulin receptors. These vesicles can also participate in the development of diabetic complications including diabetic nephropathy, diabetic cardiomyopathy, and diabetic retinopathy through a series of molecular pathways.
Recent studies have shown that stem/progenitor cell-derived EVs have potential applications in T2DM rat/mouse models via the transfer of bioactive molecules. Particularly, miRNAs transferred by these EVs played important roles in the pathological angiogenesis of T2DM, including diabetic wounds, diabetic sexual dysfunction, diabetic nephropathy, and diabetic cardiomyopathy.
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Biomarkers and Therapy
Fiandaca et al. (2015) reported that P-S396-tau, P-T181-tau and Aβ1-42 in extracts of neural-derived blood exosomes predict development of AD up to 10 years before clinical onset.
Presence of Aβ1-42 or tau in the CSF may act as a diagnostic biomarker for the early diagnosis of AD. CSF and plasma exosomes from AD patients have full-length tau, which is absent in healthy people.
Researchers refer to exosomes as “brain fuid biopsy” since they can be easily isolated from CSF [61]. In a recent study by Jia et al. (2019) found highest levels of Aβ42, total tau, and pT181-tau in neuronal exosomes of AD patients when compared to patients with amnestic MCI (aMCI) and healthy controls.
Multiple studies have found that MSC-derived exosomes are good candidates for the treatment of AD.
Exosomal delivery of neprilysin (an endopeptidase related to degradation of Aβ) from mesenchymal stem cell derived from adipose tissues provided a therapeutic tool to reduce Aβ accumulation.
Treatment with exosomes derived from MSCs were shown to reduce the activation of glial cells, and the levels of inflammatory factors involved in the regulation of the STAT3 and NF-kB pathways.
Double-edge sword
Current evidence suggests that exosomes can carry and spread toxic amyloid-beta, and hyperphosphorylated tau, between cells, and then induce apoptosis, thus contributing to the loss of neurons.
In addition, exosomes appear to possess the ability to reduce brain amyloid-beta, and tau hyperphosphorylation, and transfer neuroprotective substances between neural cells.
Q. It may be interesting to consider microglial targeting (as in, to activate) via exosomes for treatment of AD
Microglia have been shown to be both beneficial and detrimental during the onset and progression of AD. They play neuroprotective roles during the early stage of AD by promoting A𝛽 clearance, whereas they accelerate A𝛽 accumulation and contribute to neurodegeneration at later stages of disease by producing proinflammatory cytokines and downregulating genes involved in A𝛽 clearance.
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β-amyloid (Aβ) deposits activate the complement system, which, in turn, stimulates microglia to release neurotoxic materials in AD. converting microglia from M1 state to an M2 state (activation states) in which the toxic effects are reduced and their phagocytic activity toward Aβ enhanced is being studied.
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Activated microglial cells, which are the resident macrophages of the central nervous system, surround amyloid β-plaques in Alzheimer’s disease (AD) brains. Patients with AD had higher chitotriosidase activity than controls and patients with stable mild cognitive impairment (Chitotriosidase is an enzyme that is secreted by activated macrophages which plays a role in the defense against fungi, insects, and nematodes)
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Mice homozygous for lpr (lymphoproliferation) or gld (generalized lymphoproliferative disease) develop lymphadenopathy and splenomegaly and suffer from autoimmune disease. The lpr mice have a defect in a cell-surface receptor, Fas, that mediates apoptosis, while gld mice have a mutation in the Fas ligand (FasL). The Fas/FasL system is involved in activation-induced suicide of T cells.
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