Abnormal angiogenesis is a primary cause of many eye diseases, including diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity. Mesenchymal stem cells (MSCs) are currently being investigated as a treatment for several such retinal diseases based on their neuroprotective and angiogenic potentials. In this study, we evaluated the role of systemically injected human placental amniotic membrane-derived MSCs (AMSCs) on pathological neovascularization of proliferative retinopathy. We determined that AMSCs secrete higher levels of transforming growth factor-β (TGF-β1) than other MSCs, and the secreted TGF-β1 directly suppresses the proliferation of endothelial cells under pathological conditions in vitro. Moreover, in a mouse model of oxygen-induced retinopathy, intraperitoneally injected AMSCs migrated into the retina and suppressed excessive neovascularization of the vasculature via expression of TGF-β1, and the antineovascular effect of AMSCs was blocked by treatment with TGF-β1 siRNA. These findings are the first to demonstrate that TGF-β1 secreted from AMSCs is one of the key factors to suppress retinal neovascularization in proliferative retinopathy and further elucidate the therapeutic function of AMSCs for the treatment of retinal neovascular diseases.
Human placenta amniotic membrane-derived mesenchymal stem cells (AMSCs) regulate immune responses, and this property can be exploited to treat stroke patients via cell therapy. We investigated the expression profile of AMSCs cultured under hypoxic conditions and observed interesting expression changes in various genes involved in immune regulation. CD200, an anti-inflammatory factor and positive regulator of TGF-β, was more highly expressed under hypoxic conditions than normoxic conditions. Furthermore, AMSCs exhibited inhibition of pro-inflammatory cytokine expression in co-cultures with LPS-primed BV2 microglia, and this effect was decreased in CD200-silenced AMSCs. The AMSCs transplanted into the ischemic rat model of stroke dramatically inhibited the expression of pro-inflammatory cytokines and up-regulated CD200, as compared with the levels in the sham-treated group. Moreover, decreased microglia activation in the boundary region and improvements in behavior were confirmed in AMSC-treated ischemic rats. The results suggested that the highly expressed CD200 from the AMSCs in a hypoxic environment modulates levels of inflammatory cytokines and microglial activation, thus increasing the therapeutic recovery potential after hypoxic-ischemic brain injury, and further demonstrated the immunomodulatory function of AMSCs in a stroke model.
Deciphering the molecular basis of neuronal cell death is a central issue in the etiology of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the molecular basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct association with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1-mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic-HDAC3(S424E) substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage.
Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell–cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs. In this study, we tested the potential of EVs as therapeutic agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. First, we found that the mesenchymal stem-cell-derived EVs (MSC-EVs) enabled the rescue of the cytopathic effect of SARS-CoV-2 virus and the suppression of proinflammatory responses in the infected cells by inhibiting the viral replication. We found that these anti-viral responses were mediated by 17 miRNAs matching the rarely mutated, conserved 3′-untranslated regions (UTR) of the viral genome. The top five miRNAs highly expressed in the MSC-EVs, miR-92a-3p, miR-26a-5p, miR-23a-3p, miR-103a-3p, and miR-181a-5p, were tested. They were bound to the complemented sequence which led to the recovery of the cytopathic effects. These findings suggest that the MSC-EVs are a potential candidate for multiple variants of anti-SARS-CoV-2.
Traumatic brain injury (TBI), a complicated form of brain damage, is a major cause of mortality in adults. Following mechanical and structural primary insults, a battery of secondary insults, including neurotransmitter-mediated cytotoxicity, dysregulation of calcium and macromolecule homeostasis, and increased oxidative stress, exacerbate brain injury and functional deficits. Although stem cell therapy is considered to be an alternative treatment for brain injuries, such as TBI and stroke, many obstacles remain. In particular, the time window for TBI treatment with either drugs or stem cells and their efficacy is still vague. Human placenta-derived mesenchymal stem cells (hpMSCs) have received extensive attention in stem cell therapy because they can be acquired in large numbers without ethical issues and because of their immune-modulating capacity and effectiveness in several diseases, such as Alzheimer’s disease and stroke. Here, we tested the feasibility of hpMSCs for TBI treatment with an animal model and attempted to identify appropriate time points for cell treatments. Double injections at 4 and 24 h post-injury significantly reduced the infarct size and suppressed astrocyte and microglial activation around the injury. With reduced damage, double-injected mice showed enhanced anti-inflammatory- and TNF-α receptor 2 (TNFR2)-associated survival signals and suppressed pro-inflammatory and oxidative responses. In addition, double-treated TBI mice displayed restored sensory motor functions and reduced neurotoxic Aβ42 plaque formation around the damaged areas. In this study, we showed the extended therapeutic potentials of hpMSCs and concluded that treatment within an appropriate time window is critical for TBI recovery.
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.
Background: Treating aged animals with plasma of an early developmental stage (e.g, umbilical cord plasma) showed an impressive potential to slow age-associated degradation of neuronal and cognitive functions. Translating such findings to clinical realities, however, requires effective ways for assessing treatment efficacy; ideal methods should be minimally invasive, amenable for serial assays, cost-effective, and quantitative.Methods: We developed a new biosensor approach to monitor anti-aging therapy. We advanced two key sensor components: i) a blood-borne metabolite was identified as a surrogate aging-marker; and ii) a compact and cost-effective assay system was developed for on-site applications. We treated aged mice either with human umbilical cord plasma or saline; unbiased metabolite profiling on mouse plasma revealed arachidonic acid (AA) as a potent indicator associated with anti-aging effect. We next implemented a competitive magneto-electrochemical sensor (cMES) optimized for AA detection directly from plasma. The developed platform could detect AA directly from small volumes of plasma (0.5 µL) within 1.5 hour.Results: cMES assays confirmed a strong correlation between AA levels and anti-aging effect: AA levels, while decreasing with aging, increased in the plasma-treated aged mice which also showed improved learning and memory performance.Conclusions: The cMES platform will empower both pre- and clinical anti-aging research by enabling minimally invasive, longitudinal treatment surveillance; these capacities will accelerate the development of anti-aging therapies, improving the quality of individual lives.
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