MicroRNA expression profiles of neuron-derived extracellular vesicles in plasma from patients with amyotrophic lateral sclerosis

Katsu, Masataka; Hama, Yuka; Utsumi, Jun; Takashina, Ken; Yasumatsu, Hiroshi; Mori, Fumiaki; Wakabayashi, Keiji; Shoji, Mikio; Sasaki, Hidenao

doi:10.1016/j.neulet.2019.03.048

Cited by 83 publications

(91 citation statements)

References 37 publications

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“…Notably, early markers of CNS diseases can be gleaned from the characterization of neuron-, astrocyte-, oligodendrocyte-or microglia-derived EVs in the serum or the CSF. The examples of biomarkers identified from EVs in the serum or CSF include higher levels of specific miRNAs in amyotrophic lateral sclerosis [9] and traumatic brain injury [10], altered lysosomal and synaptic proteins and tau in Alzheimer's disease (AD) [11][12][13][14], increased concentration of alpha-synuclein in Parkinson's disease [15], and HMGB1 and complement-related proteins in an animal model of Gulf War Illness [16].…”

Section: Introductionmentioning

confidence: 99%

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

Kodali

Castro

Kim

et al. 2019

IJMS

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Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (hMSCs) have great promise as biologics to treat neurological and neurodegenerative conditions due to their robust antiinflammatory and neuroprotective properties. Besides, intranasal (IN) administration of EVs has caught much attention because the procedure is noninvasive, amenable for repetitive dispensation, and leads to a quick penetration of EVs into multiple regions of the forebrain. Nonetheless, it is unknown whether brain injury-induced signals are essential for the entry of IN-administered EVs into different brain regions. Therefore, in this study, we investigated the distribution of IN-administered hMSC-derived EVs into neurons and microglia in the intact and status epilepticus (SE) injured rat forebrain. Ten billion EVs labeled with PKH26 were dispensed unilaterally into the left nostril of naïve rats, and rats that experienced two hours of kainate-induced SE. Six hours later, PKH26 + EVs were quantified from multiple forebrain regions using serial brain sections processed for different neural cell markers and confocal microscopy. Remarkably, EVs were seen bilaterally in virtually all regions of intact and SE-injured forebrain. The percentage of neurons incorporating EVs were comparable for most forebrain regions. However, in animals that underwent SE, a higher percentage of neurons incorporated EVs in the hippocampal CA1 subfield and the entorhinal cortex, the regions that typically display neurodegeneration after SE. In contrast, the incorporation of EVs by microglia was highly comparable in every region of the forebrain measured. Thus, unilateral IN administration of EVs is efficient for delivering EVs bilaterally into neurons and microglia in multiple regions in the intact or injured forebrain. Furthermore, incorporation of EVs by neurons is higher in areas of brain injury, implying that injury-related signals likely play a role in targeting of EVs into neurons, which may be beneficial for EV therapy in various neurodegenerative conditions including traumatic brain injury, stroke, multiple sclerosis, and Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

Kodali

Castro

Kim

et al. 2019

IJMS

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“…This observation indicates that 3D-culture derived EV small RNAs could reflect in vivo tissue-derived EV RNAs. Although studies have been performed on EV secretion from human plasma using a 2D culture sytem 45,46 , there have been no reports on the EV secretion landscape from 3D culture and their potential for mimicking in vivo tissue system. The EV biogenesis mechanisms, molecular sorting, vesicle trafficking and releasing are still not well understood so far 7,26 .…”

mentioning

confidence: 99%

3D cell culture stimulates the secretion of in vivo like extracellular vesicles

Thippabhotla

Zhong

2019

Sci Rep

183

137

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For studying cellular communications ex-vivo, a two-dimensional (2D) cell culture model is currently used as the “gold standard”. 2D culture models are also widely used in the study of RNA expression profiles from tumor cells secreted extracellular vesicles (EVs) for tumor biomarker discovery. Although the 2D culture system is simple and easily accessible, the culture environment is unable to represent in vivo extracellular matrix (ECM) microenvironment. Our study observed that 2D- culture derived EVs showed significantly different profiles in terms of secretion dynamics and essential signaling molecular contents (RNAs and DNAs), when compared to the three-dimensional (3D) culture derived EVs. By performing small RNA next-generation sequencing (NGS) analysis of cervical cancer cells and their EVs compared with cervical cancer patient plasma EV-derived small RNAs, we observed that 3D- culture derived EV small RNAs differ from their parent cell small RNA profile which may indicate a specific sorting process. Most importantly, the 3D- culture derived EV small RNA profile exhibited a much higher similarity (~96%) to in vivo circulating EVs derived from cervical cancer patient plasma. However, 2D- culture derived EV small RNA profile correlated better with only their parent cells cultured in 2D. On the other hand, DNA sequencing analysis suggests that culture and growth conditions do not affect the genomic information carried by EV secretion. This work also suggests that tackling EV molecular alterations secreted into interstitial fluids can provide an alternative, non-invasive approach for investigating 3D tissue behaviors at the molecular precision. This work could serve as a foundation for building precise models employed in mimicking in vivo tissue system with EVs as the molecular indicators or transporters. Such models could be used for investigating tumor biomarkers, drug screening, and understanding tumor progression and metastasis.

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“…In another study comparing plasma miRNAs between 16 sALS patients and 10 healthy controls using microarray analysis, validated by qPCR, Takahashi et al (2015) found two differentially expressed miRNAs (downregulated miRNA-4299 and upregulated miRNA-4649-5p), regardless of other clinical features, concluding that these two plasma CmiRNAs had the potential to be ALS diagnosis biomarkers. By using microarray, Katsu et al (2019) identified 30 differentially expressed miRNAs in ALS plasma, including 13 upregulated and 17 downregulated miRNAs, and they further investigated the relationship between these miRNAs and ALS, and suggested that four miRNAs (miRNA-24-3p, miRNA-1268a, miRNA-3911, and miRNA-4646-5) were enriched in synaptic vesicle exocytosis and processes. Detection of these biomarkers helps get a better understanding of ALS pathophysiology and could be used for early diagnosis (Katsu et al, 2019).…”

Section: Circulating Mirnas As Biomarkers In Alsmentioning

confidence: 99%

“…Circulating miRNAs (CmiRNAs) are a class of miRNAs found in body fluids, mainly found in blood, urine, saliva, tears, milk, or amniotic fluid, which are mainly produced by the efflux of miRNAs from tissue or cells into biofluids (Jin and Xing, 2017). CmiRNAs in peripheral biofluids have been extensively investigated as biomarkers for early diagnosis and monitoring disease progression, such as Alzheimer's disease (AD) and Parkinson's disease (PD) (Hajjari et al, 2017;Li et al, 2017;Katsu et al, 2019). miRNAs are small nonprotein-encoding RNAs, usually between 19 and 25 bases in length, that can bind to RISC to regulate mRNA expression.…”

Section: Introductionmentioning

confidence: 99%

“…miRNAs are small nonprotein-encoding RNAs, usually between 19 and 25 bases in length, that can bind to RISC to regulate mRNA expression. Dysregulated miRNAs have been reported associated with the pathogenesis of MND, permitting CmiRNAs to be biomarkers in biofluids for the diagnosis and progression of MND (De Paola et al, 2019;Katsu et al, 2019). This review summarizes the progress of research on the sources and functions of CmiRNAs, the potential of diagnostic markers, and the clinical application prospects, together with problems in MNDassociated miRNA biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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Circulating MicroRNAs as Diagnostic Biomarkers for Motor Neuron Disease

Lin

Zhang

2020

Front. Neurosci.

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Motor neuron disease (MND) is a kind of neurodegenerative disease that selectively invades spinal cord anterior horn cells, brainstem motor neurons, cortical pyramidal cells and the pyramidal tract. The main clinical features are the symptoms and signs of impaired upper and lower motor neurons, manifested as muscle weakness, atrophy and pyramidal tract signs. Histopathology has shown the disappearance of pyramidal cells in the motor cortex, loss of motor neurons in the anterior horn of the spinal cord and brainstem, and degeneration of the corticospinal tract. Due to the lack of effective treatment methods, the prognosis is generally poor, so it is of great significance to confirm the diagnosis early by various means. However, the current diagnosis of MND mainly relies on the combination of clinical manifestations and neurophysiological examinations, lacking effective means of early diagnosis. Circulating microRNA (CmiRNA) is a kind of stable miRNA molecule in serum, plasma and other body fluids, which has the characteristics of distinct differential expression, sensitive detection and convenient sample collection. As a possible new biomarker of MND, CmiRNA can not only reveal the pathophysiological process of MND, but also monitor disease progression and response to drug therapy. With the development of miRNA detection technology, more and more CmiRNAs as biomarkers with potential diagnostic value have been investigated. In this review, we explored the possibility of circulating samples as different sources of biomarkers for the diagnosis of MND, analyzing the progress of CmiRNA detection techniques, and presenting potential diagnostic MND biomarkers that have been reported.

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MicroRNA expression profiles of neuron-derived extracellular vesicles in plasma from patients with amyotrophic lateral sclerosis

Cited by 83 publications

References 37 publications

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

3D cell culture stimulates the secretion of in vivo like extracellular vesicles

Circulating MicroRNAs as Diagnostic Biomarkers for Motor Neuron Disease

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