Tibetan Mesenchymal Stem Cell-derived Exosomes Alleviate Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Rats.

Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-ß1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, Western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFß pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFß1 and p-Smad2/3. Furthermore, TGFß1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFß1/Smad2/3 pathway via Nbl1.

Microdroplets Encapsulated with NFATc1-siRNA and Exosomes-Derived from MSCs Onto 3D Porous PLA Scaffold for Regulating Osteoclastogenesis and Promoting Osteogenesis.

Introduction: Osteoporotic-related fractures remains a significant public health concern, thus imposing substantial burdens on our society. Excessive activation of osteoclastic activity is one of the main contributing factors for osteoporosis-related fractures. While polylactic acid (PLA) is frequently employed as a biodegradable scaffold in tissue engineering, it lacks sufficient biological activity. Microdroplets (MDs) have been explored as an ultrasound-responsive drug delivery method, and mesenchymal stem cell (MSC)-derived exosomes have shown therapeutic effects in diverse preclinical investigations. Thus, this study aimed to develop a novel bioactive hybrid PLA scaffold by integrating MDs-NFATc1-silencing siRNA to target osteoclast formation and MSCs-exosomes (MSC-Exo) to influence osteogenic differentiation (MDs-NFATc1/PLA-Exo). Methods: Human bone marrow-derived mesenchymal stromal cells (hBMSCs) were used for exosome isolation. Transmission electron microscopy (TEM) and confocal laser scanning microscopy were used for exosome and MDs morphological characterization, respectively. The MDs-NFATc1/PLA-Exo scaffold was fabricated through poly(dopamine) and fibrin gel coating. Biocompatibility was assessed using RAW 264.7 macrophages and hBMSCs. Osteoclast formations were examined via TRAP staining. Osteogenic differentiation of hBMSCs and cytokine expression modulation were also investigated. Results: MSC-Exo exhibited a cup-shaped structure and effective internalization into cells, while MDs displayed a spherical morphology with a well-defined core-shell structure. Following ultrasound stimulation, the internalization study demonstrated efficient delivery of bioactive MDs into recipient cells. Biocompatibility studies indicated no cytotoxicity of MDs-NFATc1/PLA-Exo scaffolds in RAW 264.7 macrophages and hBMSCs. Both MDs-NFATc1/PLA and MDs-NFATc1/PLA-Exo treatments significantly reduced osteoclast differentiation and formation. In addition, our results further indicated MDs-NFATc1/PLA-Exo scaffold significantly enhanced osteogenic differentiation of hBMSCs and modulated cytokine expression. Discussion: These findings suggest that the bioactive MDs-NFATc1/PLA-Exo scaffold holds promise as an innovative structure for bone tissue regeneration. By specifically targeting osteoclast formation and promoting osteogenic differentiation, this hybrid scaffold may address key challenges in osteoporosis-related fractures.

Exosomes from SHED-MSC regulate polarization and stress oxidative indexes in THP-1 derived M1 macrophages.

OBJECTIVE: The inhibition of M1 macrophages may be interesting for targeted therapy with mesenchymal stem cell-derived Exosomes (MSC-EXOs). This study aimed to investigate the stem cells of human exfoliated deciduous teeth-derived EXOs (SHED-MSC-EXOs) effect on regulating the pro- and anti-oxidant indexes and inhibiting M1 macrophage polarization. Besides, an in-silico analysis of SHED-MSC-EXO miRNAs as the highest frequency of small RNAs in the exosomes was performed to discover the possible mechanism. METHODS: The flow cytometry analysis of CD80 and CD86 as M1-specific markers confirmed the polarization of macrophages derived from THP-1 cells. After exosome isolation, characterization, and internalization, THP-1-derived M1 macrophages were treated with SHED-MSC-EXOs. M1-specific markers and pro- and anti-oxidant indexes were evaluated. For in-silico analysis of SHED-MSC-EXOs miRNAs, initial miRNA array data of SHED-EXOs is collected from GEO, and the interaction of the miRNAs in M1 macrophage polarization (M1P), mitochondrial oxidative stress (MOS) and LPS-induced oxidative stress (LOS) were analyzed by miRWalk 3.0 server. Outcomes were filtered by 75th percentile signal intensity, score cut-off ≥0.95, minimum free energy (MEF)≤ -20 kcal/mol, and seed = 1. RESULTS: It shows a decrease in the expression of CD80 and CD81, a reduction in pro-oxidant indicators, and an increase in the anti-oxidant indexes (P < 0.05). Computational analysis showed that eight microRNAs of SHED-MSC-EXO miRNAs can bind to and interfere with the expression of candidate genes in the M1P, MOS, and LOS pathways simultaneously. CONCLUSION: SHED-MSCs-EXOs can be utilized to treat conditions related to M1 macrophage-induced diseases (M1IDs) due to their unique physical properties and ability to penetrate target cells easily.

Challenges of mesenchymal stem cells in the clinical treatment of COVID-19.

The 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought an enormous public health burden to the global society. The duration of the epidemic, the number of infected people, and the widespread of the epidemic are extremely rare in modern society. In the initial stage of infection, people generally show fever, cough, and dyspnea, which can lead to pneumonia, acute respiratory syndrome, kidney failure, and even death in severe cases. The strong infectivity and pathogenicity of SARS-CoV-2 make it more urgent to find an effective treatment. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with the potential for self-renewal and multi-directional differentiation. They are widely used in clinical experiments because of their low immunogenicity and immunomodulatory function. Mesenchymal stem cell-derived exosomes (MSC-Exo) can play a physiological role similar to that of stem cells. Since the COVID-19 pandemic, a series of clinical trials based on MSC therapy have been carried out. The results show that MSCs are safe and can significantly improve patients' respiratory function and prognosis of COVID-19. Here, the effects of MSCs and MSC-Exo in the treatment of COVID-19 are reviewed, and the clinical challenges that may be faced in the future are clarified.

Exosome Derived from Mesenchymal Stem Cells Alleviates Hypertrophic Scar by Inhibiting the Fibroblasts via TNFSF-13/HSPG2 Signaling Pathway.

Background: Mesenchymal stem cell-derived exosomes (MSC-exo) have been shown to have significant potential in wound healing and scar relief processes. According to reports, TNFSF13 and HSPG2 are associated with various fibrotic diseases. The aim of this study is to investigate how TNFSF13 and HSPG2 affect the formation of hypertrophic scar (HS) and the mechanism by which exosomes regulate HS. Methods: Immunohistochemistry, qRT-PCR, Western blot, and immunofluorescence were performed to measure TNFSF13 expression in HS skin tissues and hypertrophic scar fibroblast (HSF). HSF were treated with recombinant TNFSF13 protein and TNFSF13 siRNAs to probe the effect of TNFSF13 on the activity of HSF. The CCK-8, EdU, Transwell, and Western blot were used to investigate the role of TNFSF13 in viability, proliferation and inflammation. The influence of MSC-exo on the proliferation and function of HSF was determined by scratch and Western blot. Results: TNFSF13 was dramatically up-regulated in HS skin tissues and HSF. Recombinant TNFSF13 protein increased cell viability, proliferation, migration, fibrosis, inflammation, and the binding between TNFSF13 and HSPG2 of HSF. The opposite results were obtained in TNFSF13 siRNAs transferred HSF. Furthermore, TNFSF13 activated the nuclear factor-κB (NF-κB) signaling pathway. Silencing of HSPG2 and inhibition of NF-κB remarkably eliminated the promoting effects of TNFSF13 on cell viability, proliferation, migration, fibrosis and inflammation of HSF. MSC-exo reduced α-SMA and COL1A1 inhibited the proliferation and migration of HSF by inhibiting TNFSF13 and HSPG2. Conclusion: TNFSF13 activates NF-κB signaling pathway by interacting with HSPG2, which regulates the proliferation, migration, fibrosis and inflammatory response of HSF. Through the above mechanisms, knocking out TNFSF13 can inhibit the proliferation, migration, fibrosis and inflammatory response of HSF, whereas MSC-exo could reverse this process. These results suggest that MSC-exo alleviates HS by inhibiting the fibroblasts via TNFSF-13/HSPG2 signaling pathway.

Exosomes as a Nano-Carrier for Chemotherapeutics: A New Era of Oncology.

Despite the considerable advancements in oncology, cancer remains one of the leading causes of death worldwide. Drug resistance mechanisms acquired by cancer cells and inefficient drug delivery limit the therapeutic efficacy of available chemotherapeutics drugs. However, studies have demonstrated that nano-drug carriers (NDCs) can overcome these limitations. In this sense, exosomes emerge as potential candidates for NDCs. This is because exosomes have better organotropism, homing capacity, cellular uptake, and cargo release ability than synthetic NDCs. In addition, exosomes can serve as NDCs for both hydrophilic and hydrophobic chemotherapeutic drugs. Thus, this review aimed to summarize the latest advances in cell-free therapy, describing how the exosomes can contribute to each step of the carcinogenesis process and discussing how these nanosized vesicles could be explored as nano-drug carriers for chemotherapeutics.

MSC-EXO and tempol ameliorate bronchopulmonary dysplasia in newborn rats by activating HIF-1α.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major complication of premature infants and an important cause of morbidity and mortality. This study investigates the effect of the combination of mesenchymal stem cells-derived exosomes (MSC-EXO) and tempol on BPD and analyzes its mechanism. METHODS: MSC-EXO was extracted by centrifugation and identified by transmission electron microscopy (TEM), nanoparticle tracking analysis, and western blot analysis (WB). Tidal volume (TV), minute ventilation (MV), peak inspiratory flow (PIF), and dynamic pulmonary compliance (Cdyn) of rats were measured by BuxCo pulmonary function experimental platform. Hematoxylin-eosin staining was performed to observe the lung morphology and radical alveolar count (RAC) and mean linear intercept (MLI) were assessed. Immunofluorescence (IF) was conducted to detect the expression of CD31 and α-SMA in pulmonary blood vessels. The kits were used to calculate malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (TAOC) concentration in lung tissue. Enzyme linked immunosorbent assay was applied to detect the levels of IL-1ß, IL-17, IL-6, and IFN-γ in bronchoalveolar lavage fluid. In addition, the expressions of HIF-1α, vascular endothelial growth factor (VEGF), p-PI3K, and p-AKT were analyzed by WB and IF. RESULTS: We successfully extracted and identified MSC-EXO. In BPD rats, TV, MV, PIF, and Cdyn decreased, alveoli were simplified, and the number of interalveoli small vessels, blood vessel density decreased. Moreover, RAC, CD31, TAOC, and SOD decreased, and MLI, α-SMA, MDA, IL-1ß, IL-17, IL-6, and IFN-γ increased, which was reversed by the combination of MSC-EXO and tempol treatment after combined treatment. In addition, the expression levels of HIF-1α, VEGF, p-PI3K, and p-AKT were increased after combined treatment. CONCLUSIONS: Combined treatment could improve lung tissue injury, promote pulmonary vascular remodeling, restore lung function, and inhibit oxidative stress in BPD rats. These effects were achieved through activation of HIF-1α.

Exosomes as a nano-carrier for Chemotherapeutics: a new era of oncology

Despite the considerable advancements in oncology, cancer remains one of the leading causes of death worldwide. Drug resistance mechanisms acquired by cancer cells and inefficient drug delivery limit the therapeutic efficacy of available chemotherapeutics drugs. However, studies have demonstrated that nano-drug carriers (NDCs) can overcome these limitations. In this sense, exosomes emerge as potential candidates for NDCs. This is because exosomes have better organotropism, homing capacity, cellular uptake, and cargo release ability than synthetic NDCs. In addition, exosomes can serve as NDCs for both hydrophilic and hydrophobic chemotherapeutic drugs. Thus, this review aimed to summarize the latest advances in cell-free therapy, describing how the exosomes can contribute to each step of the carcinogenesis process and discussing how these nanosized vesicles could be explored as nano-drug carriers for chemotherapeutics.

Ethical Considerations on Clinical Transformation of MSC-Exo in Tumor Therapy / 中国医学伦理学

In recent years, basic scientific research and clinical studies on mesenchymal stem cell-derived exosome (MSC-Exo) have developed rapidly. MSC-Exo has shown good anti-tumor effects in preclinical and clinical studies. However, due to its diverse sources and functions, MSC-Exo therapy still faces many ethical issues in clinical conversion and application, including the unclear tumor types and mechanisms of action applicable to MSC-Exo, the risk/benefit issues in the process of clinical research, the lack of safety/effectiveness evaluation standards, lax access standards, and the incomplete regulatory systems. The technical guidelines and regulatory policies related to the clinical transformation and application of stem cell therapy are constantly improving. Therefore, to effectively avoid ethical risks, regulate the research and treatment related to the clinical transformation and application of MSC-Exo therapy, and improve the safety and efficacy of MSC-Exo therapy in tumor therapy, it is proposed to deepen clinical research on the relationship between MSC-Exo and tumor regulation, strengthen the risk/benefit analysis, supervise and improve the professional quality of researcher, deeply root in the principle of subjects not to be harmed, construct and perfect the relevant regulatory system, and improve the reviewing ability of the ethics committee, so as to promote the rapid clinical transformation of MSC-Exo and bring good news to cancer patients.

A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties.

Polylactic acid (PLA) is a versatile and biodegradable scaffold widely used in biomedical fields to repair tissue defects. Exosomes derived from mesenchymal stem cells (MSCs) are nano-sized extracellular vesicles, which play an important role in tissue engineering in recent years. The primary focus of this study was to develop a bioactive 3D PLA scaffold using exosome-based strategy to improve its osteogenic and immunoregulatory potential. We firstly successfully isolated MSC-derived exosomes (MSC-Exo). Morphological analysis revealed that MSC-Exo exhibits a typical cup-shaped morphology with high expression of exosomal marker CD63. MSC-Exo internalization into recipient cells were also investigated using flow cytometry and confocal laser scanning microscopy. Porous 3D PLA scaffold coated MSC-Exo were used for immunoregulatory and osteogenic testing. Exosomes released from 3D PLA scaffold were validated in RAW264.7 and hBMSCs. The cell proliferation and live/dead assay indicated high biocompatibility for PLA-Exo scaffold. Additionally, PLA-Exo scaffold could reduce the pro-inflammatory marker expression and reactive oxygen species (ROS) production, indicating potential immunoregulatory potential. It is also confirmed that PLA-Exo scaffold could potentiate osteogenic differentiation in the osteogenesis assay. In conclusion, our results demonstrate this bioactive 3D-printed PLA scaffolds with MSC-Exo modification holds immunoregulatory potential and favor osteogenic differentiation, thus having potential applications in bone tissue regeneration.

Current regenerative medicine-based approaches for skin regeneration: A review of literature and a report on clinical applications in Japan.

Current trends indicate a growing interest among healthcare specialists and the public in the use of regenerative medicine-based approaches for skin regeneration. The approaches are categorised in either cell-based or cell-free therapies and are reportedly safe and effective. Cell-based therapies include mesenchymal stem cells (MSCs), tissue induced pluripotent stem cells (iPSCs), fibroblast-based products, and blood-derived therapies, such as those employing platelet-rich plasma (PRP) products. Cell-free therapies primarily involve the use of MSC-derived extracellular vesicles/exosomes. MSCs are isolated from various tissues, such as fat, bone marrow, umbilical cord, menstrual blood, and foetal skin, and expanded ex vivo before transplantation. In cell-free therapies, MSC exosomes, MSC-derived cultured media, and MSC-derived extracellular vesicles are collected from MSC-conditioned media or supernatant. In this review, a literature search of the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus was conducted using several combinations of terms, such as 'stem', 'cell', 'aging', 'wrinkles', 'nasolabial folds', 'therapy', 'mesenchymal stem cells', and 'skin', to identify relevant articles providing a comprehensive update on the different regenerative medicine-based therapies and their application to skin regeneration. In addition, the regulatory perspectives on the clinical application of some of these therapies in Japan are highlighted.

Mesenchymal Stromal Cell-derived Exosomes Attenuate Experimental Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial Hypertension (PH) is a chronic disease that ultimately progresses to right ventricular failure and death. Until now, there is still a lack of effective treatment applied. The purpose of the present study was to observe the protective effect of Mesenchymal Stromal Cell-Derived Exosomes (MSC-EXO) against experimental Pulmonary arterial Hypertension (PH) and right ventricular failure. METHODS: All the experimental rats received an intraperitoneal injection of 50 mg/kg monocrotaline to induce PH model. Three weeks after the model was successfully established, the cell Culture Media (CM) or MSC-EXO derived from human umbilical cord was administered daily via the tail vein. All animals were randomly divided into 4 groups: Control (saline-treated), MCT-PH, MCT-CM and MCT-EXO groups. Post-operation, hemodynamic data and index of right ventricular hypertrophy (RVHI) were recorded to evaluate the inhibition of MSC-EXO on MCT-induced PH. Histology, immunohistochemistry and western blot were used to analyze the effect of MSC-EXO against vascular remodeling and further reveal the mechanism. RESULTS: In the present study, our results showed that MSC-EXO administration could significantly reduce the Right Ventricular Systolic Pressure (RVSP) and RVHI, suppress the pulmonary vascular remodeling and The Endothelial-Mesenchymal Transition (EndMT) process. CONCLUSION: Our results provided the firm information for a new method in the treatment of PH; the mechanism may be related to the inhibition of vascular remodeling and EndMT.

The protective effects of MSC-EXO against pulmonary hypertension through regulating Wnt5a/BMP signalling pathway.

The aim of the study was to explore the mechanism of mesenchymal stem cell-derived exosomes (MSC-EXO) to protect against experimentally induced pulmonary hypertension (PH). Monocrotaline (MCT)-induced rat model of PH was successfully established by a single intraperitoneal injection of 50 mg/kg MCT, 3 weeks later the animals were treated with MSC-EXO via tail vein injection. Post-operation, our results showed that MSC-EXO could significantly reduce right ventricular systolic pressure (RVSP) and the right ventricular hypertrophy index, attenuate pulmonary vascular remodelling and lung fibrosis in vivo. In vitro experiment, the hypoxia models of pulmonary artery endothelial cell (PAEC) and pulmonary vascular smooth muscle cell (PASMC) were used. We found that the expression levels of Wnt5a, Wnt11, BMPR2, BMP4 and BMP9 were increased, but ß-catenin, cyclin D1 and TGF-ß1 were decreased in MSC-EXO group as compared with MCT or hypoxia group in vivo or vitro. However, these increased could be blocked when cells were transfected with Wnt5a siRNA in vitro. Taken together, these results suggested that the mechanism of MSC-EXO to prevent PH vascular remodelling may be via regulation of Wnt5a/BMP signalling pathway.

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats.

BACKGROUND: Restenosis is a serious problem in patients who have undergone percutaneous transluminal angioplasty. Endothelial injury resulting from surgery can lead to endothelial dysfunction and neointimal formation by inducing aberrant proliferation and migration of vascular smooth muscle cells. Exosomes secreted by mesenchymal stem cells have been a hot topic in cardioprotective research. However, to date, exosomes derived from mesenchymal stem cells (MSC-Exo) have rarely been reported in association with restenosis after artery injury. The aim of this study was to investigate whether MSC-Exo inhibit neointimal hyperplasia in a rat model of carotid artery balloon-induced injury and, if so, to explore the underlying mechanisms. METHODS: Characterization of MSC-Exo immunophenotypes was performed by electron microscopy, nanoparticle tracking analysis and western blot assays. To investigate whether MSC-Exo inhibited neointimal hyperplasia, rats were intravenously injected with normal saline or MSC-Exo after carotid artery balloon-induced injury. Haematoxylin-eosin staining was performed to examine the intimal and media areas. Evans blue dye staining was performed to examine re-endothelialization. Moreover, immunohistochemistry and immunofluorescence were performed to examine the expression of CD31, vWF and α-SMA. To further investigate the involvement of MSC-Exo-induced re-endothelialization, the underlying mechanisms were studied by cell counting kit-8, cell scratch, immunofluorescence and western blot assays. RESULTS: Our data showed that MSC-Exo were ingested by endothelial cells and that systemic injection of MSC-Exo suppressed neointimal hyperplasia after artery injury. The Evans blue staining results showed that MSC-Exo could accelerate re-endothelialization compared to the saline group. The immunofluorescence and immunohistochemistry results showed that MSC-Exo upregulated the expression of CD31 and vWF but downregulated the expression of α-SMA. Furthermore, MSC-Exo mechanistically facilitated proliferation and migration by activating the Erk1/2 signalling pathway. The western blot results showed that MSC-Exo upregulated the expression of PCNA, Cyclin D1, Vimentin, MMP2 and MMP9 compared to that in the control group. Interestingly, an Erk1/2 inhibitor reversed the expression of the above proteins. CONCLUSION: Our data suggest that MSC-Exo can inhibit neointimal hyperplasia after carotid artery injury by accelerating re-endothelialization, which is accompanied by activation of the Erk1/2 signalling pathway. Importantly, our study provides a novel cell-free approach for the treatment of restenosis diseases after intervention.

Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice.

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.