Biology subjects

Kim, C.-H.

Publications and source records attributed to Kim, C.-H..

At least 19 recordsLinked to original sources

bioRxiv2026

Synaptic engram underlies memory

Memory encoding cells, or engram cells, are sparsely distributed across the brain. Recent findings have shown that memory formation coincides with the strengthening of interregional synaptic connectivity between engram ensembles. However, whether this learning-induced synaptic reorganization causally supports memory, independently or in concert with heterosynaptic and intrinsic plasticity, remains elusive. Here we developed optically implemented spike-timing-dependent plasticity (oSTDP), which induces synaptic depression selectively at target synapses by controlling the relative timing of pre- and postsynaptic activity. In vivo application of oSTDP to the synapses between entorhinal cortex (EC) and dentate gyrus (DG) engram cells caused a significant synaptic depression and the resultant memory impairment. Our results demonstrate that plasticity of functional connectivity between memory-encoding ensembles causally underlies memory.

neuroscience↗

bioRxiv2026

The not-so-great speciator: Systematics and species limits in a rapid radiation, the Asiatic white-eye complex (Zosterops spp.)

Abstract/SummaryHere we untangle the systematics of the Asiatic white-eye complex (Zosterops spp.) to better understand the early stages of a recent island radiation. We adopt an integrative approach involving allelic data, genome-scale single nucleotide polymorphisms (SNPs), and museum-based morphometrics coupled with a comprehensive sampling to provide the most holistic understanding of the group to date. The island lineages of Asiatic white-eyes across Indonesia, the Philippines, East Asia, the adjacent oceanic islands of the Western Pacific underwent a deep split separating Zosterops everetti and Z. nigrorum in the Phillippines from a very rapid radiation including Z. japonicus, Z. meyeni, and Z. montanus in the Philippines, Japan, and Indonesia. Z. nigrorum catarmanensis on Camiguin South in the Philippines was found to be nested within Z. montanus and a species limit between Z. nigrorum populations on Panay and Luzon was strongly supported. Phylogenetic splits and population structure were detected within the clade containing Z. japonicus, Z. meyeni, and Z. montanus. A well-supported split separates a northern group including Northern Philippines Z. montanus subspecies, Z. meyeni, and Z. japonicus from the southerly Z. montanus taxa. This creates a paraphyletic Z. montanus. However, based on speciation rates within the broader Asiatic white-eye clade this break likely does not yet represent evolutionarily independent species lineages. Morphological evolution is taking place within the Asiatic white-eyes especially within the robust, large-billed subspecies of Z. japonicus on the oceanic islands of Japan and in the newly identified yellow-morph of Z. montanus on Camiguin South.

evolutionary biology↗

bioRxiv2026

The Vector Competence and Vectorial Capacity of Aedes albopictus for Ross River Virus in the United States as a Function of Temperature

Ross River virus (RRV) is a medically significant arbovirus endemic to Australia where it causes an average of 5000 reported human cases per year. Due to concern for possible transmission outside of its endemic range, we examined the vector competence and vectorial capacity of RRV by Aedes albopictus (Skuse 1894) to contribute to risk assessments for outbreaks in the United States. We tested Ae. albopictus mosquitoes exposed to RRV at three temperatures and five time points post-infection for infection and dissemination. We also collected saliva from exposed individuals incubated at the same three temperatures to determine the presence of viral RNA. Additionally, we assessed the impact of viral infection on life expectancy as a function of temperature. Rates of infection were unaffected by time and temperature and 89.3% of individuals were infected. 85-100% of infected individuals displayed dissemination by day 7 at all temperatures. The extrinsic incubation period as determined by the saliva collection was approximately 6 days and 78.6-100% of individuals tested expressed salivary viral RNA at some point in the experiment which is comparable to the rates of overall infection. The vectorial capacity of RRV with Ae. albopictus as a vector ranged from 10.23-23.37 indicating that these mosquitoes are competent potential vectors for RRV. Due to prior outbreaks RRV has caused outside of its endemic range, these findings warrant further investigation in the transmission potential of RRV in the United States. Author SummaryThe last 30 years has seen a steady increase in mosquito-borne illness globally, much of which has been driven by viruses such as dengue establishing in new areas as a consequence of the spread of its primary vectors and environmental changes. In order to mitigate the continued increase in the prevalence of mosquito-borne illness, it is necessary to determine which viruses are likely to spread beyond their native range. Ross River virus (RRV) is a mosquito-borne virus which, while nonlethal, commonly causes a litany of debilitating side-effects for extended periods of time. RRV is endemic to Australia, however the recent introduction of a known RRV vector to California as well as the widespread prevalence of a suspected RRV vector, Ae. albopictus, across the country, could prime RRV for an outbreak in the continental United States. As part of a risk assessment for the outbreak potential of RRV in the continental United States, we investigated the vector competence and vectorial capacity of Ae. albopictus. We find that this species is a competent vector for this virus across a range of relevant temperatures.

ecology↗

bioRxiv2025

Advancing Wildlife Image Analysis: A Graph Attention Contrastive Learning Approach for Region-Specific Mammal Classification

1. Camera traps have become a cornerstone of wildlife ecological research, yet the manual analysis of the millions of images they generate requires substantial time and resources. Deep learning-based automation has emerged as a promising solution, existing global general-purpose models exhibit limitations in precisely recognizing local endemic species and adapting to unique local ecosystems. 2. This study developed a high-performance classification model optimized for native species. A large-scale "Korean Wildlife Dataset" was constructed from data collected across diverse domestic habitats, and a novel architecture was proposed to overcome limitations of conventional CNNs. The proposed Graph Attention Contrastive Learning (GACL) model is structured as a two-stage pipeline. Stage one employs YOLOv5 and MegaDetector to detect animals, humans, and vehicles, filtering valid images. Stage two performs fine-grained species classification. GACL captures structural relationships among object parts using a Graph Attention Transformer (GAT) and aligns semantic correspondence between images and textual descriptions via Parallel Contrastive Learning, enabling deeper understanding beyond simple visual features. 3. Evaluation on an independent test set demonstrated that the proposed model robust classification performance with an overall accuracy of 96.83% across four classes (Wildboar, Goral, Deers, and Other). Notably, in a comparative analysis against a global general-purpose model, our model showed distinct advantages in the precise recognition of endemic species. Furthermore, it exhibited a lower false positive rate in identifying animals in empty images, confirming its potential to enhance the efficiency of the data cleaning process. 4. Beyond technical accuracy, this study highlights that region-specific AI models that reflect local ecological characteristics can provide substantial practical value for wildlife monitoring and biodiversity conservation. Future work will require continuous efforts in data diversification and model lightweighting to further improve model robustness and practicality.

ecology↗

bioRxiv2025

Integrative Analysis of Proteomics and Metabolomics Reveals Impacts of Sam2 Knockout on Autism Spectrum Disorders

Neurokine Sam2 deficiency is associated with behavioral abnormalities including heightened anxiety and fear responses across evolutionarily conserved model organisms. Here, we employed an integrated proteomics and metabolomics approach using liquid chromatography-mass spectrometry (LC-MS) to elucidate molecular signatures associated with autism spectrum disorder (ASD) in Sam2 knockout mice. Comparative analysis of blood plasma samples from Sam2 knockout and wild-type mice revealed substantial alterations in both proteomic and metabolomic profiles. Proteomic analysis identified 68 differentially expressed proteins (comprising 102 peptides), with notable upregulation of complement component C1qc and downregulation of apolipoprotein A1 (Apoa1), implicating dysregulation of complement cascade pathways. Metabolomic profiling uncovered 15 significantly altered metabolites: nine upregulated species including D-glucuronic acid and 5,10-Methylenetetrahydrofolate, and six downregulated metabolites including folinic acid and acetate. Integrative pathway analysis revealed perturbations in glycolysis/gluconeogenesis and glycerophospholipid metabolism, providing mechanistic insights into the molecular consequences of Sam2 deficiency. These findings identify potential biomarkers for anxiety-related disorders and ASD while advancing our understanding of the complex interplay between genetic alterations and proteomic-metabolomic networks in neurodevelopmental conditions. Our results establish a foundation for developing targeted therapeutic interventions and highlight the utility of multi-omics approaches in dissecting the molecular basis of behavioral disorders.

systems biology↗

bioRxiv2025

Infection and host-feeding patterns of West Nile virus vectors varies by urban greenspace composition

Greenspaces are integral to the urban environment and affect climate resilience, yet the extent to which they affect mosquito and West Nile virus (WNV) host populations and behavior is not clear. To address this question, we collected mosquitoes along a transect spanning a range of urban development. Mosquitoes were tested for West Nile virus, and the host species that were fed on determined for blood-fed specimens. Bird counts and camera traps were used to assess avian and mammal species availability. Different components that contribute to WNV transmission intensity responded to different landcover variables. Abundance of Culex mosquitoes was most strongly tied to impervious surface, while prevalence of infection was associated with increasing amounts of turf grass. The amount of turf was itself correlated with a measure of avian community reservoir competence. Blood meal analysis suggested the majority of blood meals in the ornithophagic species Cx. pipiens and Cx. restuans came from American robins and northern cardinals, with the latter in particular being overutilized relative to their abundance in sites with higher WNV prevalence. This work furthers our understanding of how the design of urban greenspaces could benefit from consideration of vector-host-virus interactions.

ecology↗

bioRxiv2025

Growth hormone is required for hippocampal engram cell maturation

Memory is thought to be stored in a sparse population of neurons or synapses 1. These neurons or synapses collectively termed the engram are necessary and sufficient for memory recall 2,3. Learning induces synaptic strengthening in engram cells at both pre- and postsynaptic sites 4,5. However, the critical time window and the molecule related to the induction of such synaptic changes are unknown. Here we show that the initial translation plays a key role in engram maturation by facilitating pre- and postsynaptic strengthening and that growth hormone (GH) is required to induce this process in the Dentate Gyrus. Using anisomycin, a protein synthesis inhibitor, we found that blocking the initial and the subsequent second wave of translation arrests the maturation of engram cells. Revisiting our hippocampal translatome during memory formation 6 proposed GH as a mediator of engram maturation. Overexpression of the dominant negative (G118R) GH blocked the maturation of the hippocampal engram cell 7. Facilitating activity-dependent GH uptake by injecting recombinant human GH (rhGH) into the animal rescued the arrestment caused by anisomycin. Together, our findings propose GH as a key mediator of hippocampal engram cell maturation.

neuroscience↗

bioRxiv2025

Protein Synthesis Blockade Prevents Fear Memory Reactivation via Inhibition of Engram Synapse Strengthening

Memory relies on ensembles of engram cells in the brain. While previous studies have established the existence of these cells, the relationship between cellular and synaptic activity remains unclear. To address this, we applied the dual e-GRASP technique in mice to examine synaptic connectivity between the ventral CA1 and the basal amygdala during memory formation. We found that contextual fear conditioning increased engram-to-engram synapse (engram synapse) density and induced structural potentiation, underscoring their importance in associative memory. Additionally, we investigated the role of protein synthesis in memory formation by inducing retrograde amnesia using anisomycin, a protein synthesis inhibitor. Mice injected with anisomycin once (1xANI) showed impaired natural recall but still displayed fear responses upon optogenetic reactivation of engram cells. In contrast, mice that received four anisomycin injections over six hours (4xANI) showed significantly impaired natural recall and failed to exhibit fear responses upon optogenetic reactivation. This behavioural phenotype was correlated with synaptic changes: 1xANI mice exhibited no significant reduction in engram synapse density but had significantly smaller spine sizes, whereas 4xANI mice showed both a significant reduction in engram synapse density and spine size. Our results indicate that protein synthesis inhibition significantly reduces engram synapse density and spine size, changes that correlate with reductions in fear memory during both natural recall and artificial reactivation.

neuroscience↗

bioRxiv2024

Spatiotemporal regulation by downstream genes of Prok2 in olfactory system: from development to function

Olfaction is important for the quality of life; however, in Kallmann syndrome (KS), defective development results in olfactory dysfunction. The mechanism underlying olfactory development, especially in the olfactory epithelium (OE), which detects olfactory signals, remains unclear. Mutations in PROK2, which encodes prokineticin-2, occur in approximately 9% of the KS patients with olfactory defects. In this study, we examined olfactory function and analyzed the causes of olfactory dysfunction based on spatiotemporal development and gene expression changes in Prok2 knockout (KO) model mice with KS. Adult Prok2 KO mice exhibited reduced ability to detect olfactory signals. Maturation of olfactory sensory neurons (OSNs) in the OE and formation of glomeruli in the olfactory bulb (OB) in adult Prok2 KO mice were disrupted, thus causing olfactory dysfunction. Molecular analysis of Prok2 KO mice during embryonic development revealed abnormal development of OB layers and reduced differentiation to mature OSNs in the OE, which caused defects in the entire olfactory system. Downstream signaling genes of Prok2, including intermediate filament genes and genes expressed in the putative OB, mediated olfactory system organization. Our findings reveal the role of Prok2 in olfactory system organization, providing insights into the mechanisms through which olfactory development defects translate to olfactory function.

developmental biology↗

bioRxiv2024

Mechanistic evidence of widespread insecticide resistance among Illinois West Nile virus vectors (Culex pipiens and Culex restuans)

BackgroundMosquitoes are major vectors of arboviruses and other vector-borne diseases, making them a significant public health concern worldwide. Mitigation of arboviral outbreaks relies largely on the use of insecticides, but the effectiveness of such responses is threatened by the evolution of insecticide resistance. Monitoring mosquito susceptibility to different insecticides is therefore vital for informed decisions regarding outbreak responses. In this study, we elucidate the patterns of resistance to two insecticide classes within the primary vectors of West Nile virus in the northeast and midwestern regions of the continental United States, Culex pipiens and Culex restuans. Methodology/Principal FindingsEgg collections were performed throughout Illinois from 2018-2020, and adults were tested for insecticide resistance to permethrin and malathion. Individuals from each sampling location were sequenced to determine the presence of kdr target-site mutations, and biochemical assays were performed to determine increases in detoxification enzymes and insensitive acetylcholinesterase. Results from the bottle assays indicate variable resistance rates in Illinois, however lowered mortality was found in most of the regions that were tested. The kdr mutation (L1014F) was present in 50% of Culex pipiens sequenced, and more prevalent in southern Illinois compared with northern and central (p < 0.001). Different mechanisms were predictive of resistance by species and insecticide, with permethrin resistance being affected by kdr-allele frequency and oxidase levels and malathion resistance by - and {beta}-esterases in Cx. pipiens. For Cx. restuans -esterase and oxidase levels were predictive of permethrin resistance while {beta}-esterase and insensitive acetylcholinesterase levels were predictive of malathion resistance. Conclusions/SignificanceWe documented variation in insecticide resistance levels that appear to be driven by population differences in kdr mutation rates and metabolic resistance mechanisms. The presence of different mechanisms in species and regions has implications for approaches to resistance management and highlights the need to implement and maintain insecticide resistance monitoring practices. Author SummaryMosquitoes are the vectors of many major diseases including malaria, dengue, yellow fever, zika, and West Nile virus. Insecticides are often used to control mosquitoes and the outbreaks they cause. However, evidence has shown that populations of different mosquito species worldwide have developed resistance to our most common insecticides. This study shows that West Nile virus vectors in Illinois, (Culex pipiens and Culex restuans) are no exception to this trend. Egg collections were made throughout the state during the 2018-2020 field seasons and the resulting adults were tested for resistance to two common insecticides using the CDCs bottle bioassay protocol. The results indicate that rates of resistance vary throughout the state and population differences in resistance mechanisms are driving this variation.

ecology↗

bioRxiv2024

Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function in mice that will pave the way for future molecular studies into DESSH. These studies present two new animals that begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

neuroscience↗

bioRxiv2024

Human umbilical mesenchymal stem cell-derived mitochondria ameliorate maternal phenotype by improving placental mitochondria and vascular function in angiotensin II-induced preeclampsia rat

BackgroundMitochondrial transplantation (Mito-T) is a novel therapeutic strategy targeting ischemic cardiovascular diseases. Here, we tested the efficacy of human umbilical mesenchymal stem cell-derived mitochondria transplantation (Mito-T) on a rat model of PE. MethodsPE was induced by infusing angiotensin II (Ang II) to SD pregnancy rats on gestation day 8 (GD 8). Mito-T (100 g/l) was injected via jugular vein on GD 14. FindingsOn GD 20, PE rats showed high blood pressure, kidney and placental vascular abnormalities, reduced placental and fetal weights. Injected Mito-T was distributed intensively in the kidney, uterus and placenta of PE rats. Importantly, Mito-T reversed clinical manifestations of PE, restored placental abnormalities and reduced serum sFLT-1 levels and sFLT-1/PlGF ratio. In the placental mitochondria, Mito-T increased ETC complexes (complex I-V), improved mitochondrial membrane potential, ATP synthase and citrate synthase activities and biogenesis markers (PGC-1, TFAM, NRF1) and reduced ROS production. Mito-T increased mitochondrial fusion proteins (OPA1, MFN1 and MFN2), reduced mitochondrial fission proteins (DRP1 and FIS1) and mitophagy proteins (PINK, BNIP3, BNIP3L, FUNDC1), restored sFLT-1 regulating calcineurin-NFAT-dependent pathways in the placental tissue, primary trophoblast cells and Bewo cell line. Furthermore, eNOS, nNOS and AT2R mRNA and protein expressions were restored in placenta and trophoblast cells after Mito-T. InterpretationThis is the first study of PE treatment with Mito-T. Mito-T reverses pathological phenotypes of PE rats by improving placental mitochondrial and vascular function. The results provide proofs of concept of Mito-T as a potential therapeutic strategy for reducing maternal and fetal risks in PE patients. FundingThis work is supported by Korean National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A2C1005720, NRF-2023R1A2C1005720), BK21 FOUR education program, Korean Society of Hypertension (Grant number KSH-R-2020), National Natural Science Foundation of China (NSFC 31660284, NSFC31860288).

pathology↗

bioRxiv2022

Statistically unbiased prediction enables accurate denoising of voltage imaging data

Here we report SUPPORT (Statistically Unbiased Prediction utilizing sPatiOtempoRal information in imaging daTa), a self-supervised learning method for removing Poisson-Gaussian noise in voltage imaging data. SUPPORT is based on the insight that a pixel value in voltage imaging data is highly dependent on its spatially neighboring pixels in the same time frame, even when its temporally adjacent frames do not provide useful information for statistical prediction. Such spatiotemporal dependency is captured and utilized to accurately denoise voltage imaging data in which the existence of the action potential in a time frame cannot be inferred by the information in other frames. Through simulation and experiments, we show that SUPPORT enables precise denoising of voltage imaging data while preserving the underlying dynamics in the scene.

neuroscience↗

bioRxiv2022

Comparison of thigh muscle characteristics between older and young women using tensiomyography

Tensiomyography is a non-invasive method of evaluating neuromuscular function through skeletal muscle contraction. The objective of this study was to compare the thigh muscle characteristics of older and young women using tensiomyography. Nineteen older and fifteen young women without musculoskeletal diseases were included. For the quadriceps, the bilateral vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF) and for the hamstrings, the bilateral semitendinosus (ST) and biceps femoris (BF) were measured. Result variables--maximal displacement (Dm), contraction time (Tc), and contraction velocity (Vc)--were compared. Dm values of the hamstrings of both legs and their summed values were significantly smaller in older women than in young women; no difference was found in the Dm values of the quadriceps. Tc and Vc of the hamstrings, VM, and VL were longer and slower, respectively, in older women than in young women. There were no significant differences in the Dm, Tc, or Vc of the RF between older and young women. Decreased Dm of the hamstrings in older women occurred due to changes in muscle function, but not muscle mass. The changes in the Tc of the hamstrings, VM, and VL indicate that type II muscle fibers were converted to type I in older women. There was no difference in RF between older and young women, implying that the RF is not affected by age. Our findings indicate that resistance exercises, which preserve the type II fibers, and flexibility exercises, which reduce stiffness, are appropriate for the lower extremity in older women.

biophysics↗

bioRxiv2022

Whole-brain mapping of effective connectivity by fMRI with cortex-wide patterned optogenetics

Functional magnetic resonance imaging (fMRI) with optogenetic neural manipulation is a powerful tool that enables brain-wide mapping of effective functional networks. To achieve flexible manipulation of neural excitation throughout the mouse cortex, we incorporated spatiotemporal programmable optogenetic stimuli generated by a digital micromirror device into an MR scanner via an optical fiber bundle for the first time. This approach offered versatility in space and time in planning the photostimulation pattern, combined with in situ optical imaging and cell-type or circuit-specific genetic targeting in individual mice. Brain-wide effective connectivity obtained by fMRI with optogenetic stimulation of atlas-based cortical regions is generally congruent with anatomically defined axonal tracing data but is affected by the types of anesthetics that act selectively on specific connections. fMRI combined with flexible optogenetics opens a new path to investigate dynamic changes in functional brain states in the same animal through high-throughput brain-wide effective connectivity mapping.

neuroscience↗

bioRxiv2022

Trogocytic-molting of T-cell microvilli controls T-cell clonal expansion

Internalization of the T-cell antigen receptor (TCR) is intimately linked to T-cell activation: a phenomenon thought to be related to the "exhaustion" of T-cell responses. To date, however, no report has considered that during physical interaction with cognate antigen-presenting cells, T cells release many TCRs via T-cell microvilli particles, which are derived from finger-like membrane structures (microvilli) in a combined process of trogocytosis and enzymatic vesiculation and correspond with the loss of membrane TCRs and many external membrane components. Surprisingly, in contrast to TCR internalization, this event leads to rapid upregulation of surface TCRs and remarkable metabolic reprogramming of cholesterol and fatty acids synthesis to meet the demands of clonal expansion, which drives multiple rounds of division and cell survival. We called this event "trogocytic-molting," which represents an intrinsic molecular basis of T-cell clonal expansion by which T cells gain increased sensitivity to low antigen concentrations. TEASER"Trogocytic-molting," led to the rapid upregulation of surface TCRs and tremendous metabolic reprogramming to meet the demands of clonal expansion.

immunology↗

bioRxiv2021

G9a/GLP methyltransferases inhibit autophagy by methylation-mediated ATG12 protein degradation

Previous studies have shown that G9a, a lysine methyltransferase, inhibits autophagy by repressing the transcription of autophagy genes. Here, we demonstrate a novel mechanism whereby G9a/GLP inhibit autophagy through post-translational modification of ATG12, a protein critical for the initiation of autophagosome formation. Under non-stress conditions, G9a/GLP directly methylate ATG12. The methylated ATG12 undergoes ubiquitin-mediated protein degradation, thereby inhibiting autophagy induction. By contrast, under stress conditions that elevate intracellular Ca2+ levels, the activated calpain system cleaves the G9a/GLP proteins, leading to G9a/GLP protein degradation. The reduced G9a/GLP levels allow ATG12 to accumulate and form the ATG12-ATG5 conjugate, thus expediting autophagy initiation. Collectively, our findings reveal a distinct signaling pathway that links cellular stress responses involving Ca2+/calpain to G9a/GLP-mediated autophagy regulation. Moreover, our model proposes that the methylation status of ATG12 is a molecular rheostat that controls autophagy induction.

molecular biology↗

bioRxiv2020

Antiviral effects of miRNAs in extracellular vesicles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mutations in SARS-CoV-2 RNA virus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 2019 (COVID-19). No treatment is available. Micro-RNAs (miRNAs) in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are potential novel therapeutic agents because of their ability to regulate gene expression by inhibiting mRNA. Thus, they may degrade the RNA genome of SARS-CoV-2. EVs can transfer miRNAs to recipient cells and regulate conditions within them. MSC-EVs harbor major therapeutic miRNAs that play important roles in the biological functions of virus-infected host cells. Here, we examined their potential impact on viral and immune responses. MSC-EVs contained 18 miRNAs predicted to interact directly with the 3 UTR of SARS-CoV-2. These EVs suppressed SARS-CoV-2 replication in Vero E6 cells. In addition, five major miRNAs suppressed virus activity in a luciferase reporter assay by binding the 3 UTR. MSC-EVs showed strong regenerative effects and potent anti-inflammatory activity which may prevent lethal cytokine storms. We confirmed that EVs regulated inflammatory responses by several cell types, including human brain cells that express the viral receptor ACE2, suggesting that the brain may be targeted by SARS-CoV-2. miRNAs in MSC-EVs have several advantages as therapeutic agents against SARS-CoV-2: 1) they bind specifically to the viral 3 UTR, and are thus unlikely to have side effects; 2) because the 3 UTR is highly conserved and rarely mutates, MSC-EV miRNAs could be used against novel variants arising during viral replication; and 3) unique cargoes carried by MSC-EVs can have diverse effects, such as regenerating damaged tissue and regulating immunity.

molecular biology↗