Study on the Therapeutic Effects and Mechanisms of Human Mesenchymal Stem Cell-Derived Exosomes Carrying NGF Gene in Treating Ischemic Stroke in Rats

Objective:To investigate the therapeutic effects and mechanisms of human mesenchymal stem cell-derived exosomes(hMSCs-Exo)carrying the NGF gene in treating ischemic stroke in rats,aiming to provide new insights and treatment methods for ischemic stroke therapy.Methods:After successful construction of the cerebral ischemia model in 40 male SPF-grade SD rats aged 6-8 weeks,the model rats were randomly divided into 4 groups:Sham group,PBS group,hMSCs-Exo group,and NGF-hMSCs-Exo group,with 10 rats in each group.The rat MCAO model was prepared using the classic filament method,and NGF-hMSCs-Exo were injected via the tail vein into the MCAO model rats.The expression of the NGF gene in brain ischemic tissues,neuronal regeneration,and rat neurological function recovery were observed using TTC staining,memory function evaluation,Western blot,qRT-PCR,and other methods.Results:Compared with the Sham group,neurological deficits were significant in the PBS group(P<0.01).Compared with the PBS group,neurological scores improved in the hMSCs-Exo group and NGF-hMSCs-Exo group(P<0.05).Compared with the hMSCs-Exo group,the improvement in neurological deficits was more significant in the NGF-hMSCs-Exo group(P<0.05).The infarct area after NGF-hMSCs-Exo intervention was significantly reduced(P<0.05)compared with the Sham group.Compared with the PBS group,relative expression levels of NGF mRNA and protein decreased,while Caspase-3 mRNA and protein expression significantly increased in the PBS group(P<0.01).Compared with the PBS group and hMSCs-Exo group,there were differences in NGF and Caspase-3 mRNA and protein expression in the NGF-hMSCs-Exo group rat brain tissues(P<0.05).Conclusion:Treatment with human mesenchymal stem cell-derived exosomes carrying the NGF gene improves cognitive function and exerts protective effects on SD rats while inhibiting apoptotic levels in cells.

Mesenchymal stem cell-derived exosomes regulate microglia phenotypes:a promising treatment for acute central nervous system injury

There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.Mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.

Exosomes from circ-Astn1-modified adipose-derived mesenchymal stem cells enhance wound healing through miR-138-5p/SIRT1/FOXO1 axis regulation

BACKGROUND Wound healing impairment is a dysfunction induced by hyperglycemia and its effect on endothelial precursor cells(EPCs)in type 2 diabetes mellitus.There is increasing evidence showing that exosomes(Exos)derived from adipose-derived mesenchymal stem cells(ADSCs)exhibit the potential to improve endothelial cell function along with wound healing.However,the potential therapeutic mechanism by which ADSC Exos contribute to wound healing in diabetic mice remains unclear.AIM To reveal the potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice.METHODS Exos from ADSCs and fibroblasts were used for high-throughput RNA sequencing(RNA-Seq).ADSC-Exo-mediated healing of full-thickness skin wounds in a diabetic mouse model was investigated.We employed EPCs to investigate the therapeutic function of Exos in cell damage and dysfunction caused by high glucose(HG).We utilized a luciferase reporter(LR)assay to analyze interactions among circular RNA astrotactin 1(circ-Astn1),sirtuin(SIRT)and miR-138-5p.A diabetic mouse model was used to verify the therapeutic effect of circ-Astn1 on Exo-mediated wound healing.RESULTS High-throughput RNA-Seq analysis showed that circ-Astn1 expression was increased in ADSC Exos compared with Exos from fibroblasts.Exos containing high concentrations of circ-Astn1 had enhanced therapeutic effects in restoring EPC function under HG conditions by promoting SIRT1 expression.Circ-Astn1 expression enhanced SIRT1 expression through miR-138-5p adsorption,which was validated by the LR assay along with bioinformatics analyses.Exos containing high concentrations of circ-Astn1 had better therapeutic effects on wound healing in vivo compared to wild-type ADSC Exos.Immunofluorescence and immunohistochemical investigations suggested that circ-Astn1 enhanced angiopoiesis through Exo treatment of wounded skin as well as by suppressing apoptosis through promotion of SIRT1 and decreased forkhead box O1 expression.CONCLUSION Circ-Astn1 promotes the therapeutic effect of ADSC-Exos and thus improves wound healing in diabetes via miR-138-5p absorption and SIRT1 upregulation.Based on our data,we advocate targeting the circ-Astn1/miR-138-5p/SIRT1 axis as a potential therapeutic option for the treatment of diabetic ulcers.

Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19

Coronavirus disease 2019(COVID-19)is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).SARS-CoV-2 infection typically presents with fever and respiratory symptoms,which can progress to severe respiratory distress syndrome and multiple organ failure.In severe cases,these complications may even lead to death.One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response.Therefore,suppressing the overactive immune response may be an effective strategy for treating COVID-19.Mesenchymal stem cells(MSCs)and their derived exosomes(MSCs-Exo)have potent homing abilities,immunomodulatory functions,regenerative repair,and antifibrotic effects,promising an effective tool in treating COVID-19.In this paper,we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19.We also summarize relevant recent clinical trials,including the source of cells,the dosage and the efficacy,and the clinical value and problems in this field,providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

Mechanism of adipose-derived mesenchymal stem cell exosomes in the treatment of heart failure

BACKGROUND Heart failure(HF)is a global health problem characterized by impaired heart function.Cardiac remodeling and cell death contribute to the development of HF.Although treatments such as digoxin and angiotensin receptor blocker drugs have been used,their effectiveness in reducing mortality is uncertain.Researchers are exploring the use of adipose-derived mesenchymal stem cell(ADMSC)exosomes(Exos)as a potential therapy for HF.These vesicles,secreted by cells,may aid in tissue repair and regulation of inflammation and immune responses.However,further investigation is needed to understand the specific role of these vesicles in HF treatment.AIM To investigate the mechanism of extracellular vesicles produced by ADMSC s in the treatment of HF.METHODS Exogenous surface markers of ADMSCs were found,and ADMSCs were cultured.RESULTS The identification of surface markers showed that the surface markers CD44 and CD29 of adipose-derived stem cells(ADSCs)were well expressed,while the surface markers CD45 and CD34 of ADSCs were negative,so the cultured cells were considered ADSCs.Western blotting detected the Exo surface marker protein,which expressed CD63 protein but did not express calnexin protein,indicating that ADSC-derived Exos were successfully extracted.CONCLUSION The secretion of MSCs from adipose tissue can increase ATP levels,block cardiomyocyte apoptosis,and enhance the heart function of animals susceptible to HF.The inhibition of Bax,caspase-3 and p53 protein expression may be related to this process.

Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine

Mesenchymal stem cells(MSCs)are multipotent stem cells with marked potential for regenerative medicine because of their strong immunosuppressive and regenerative abilities.The therapeutic effects of MSCs are based in part on their secretion of biologically active factors in extracellular vesicles known as exosomes.Exosomes have a diameter of 30-100 nm and mediate intercellular communication and material exchange.MSC-derived exosomes(MSC-Exos)have potential for cell-free therapy for diseases of,for instance,the kidney,liver,heart,nervous system,and musculoskeletal system.Hence,MSC-Exos are an alternative to MSCbased therapy for regenerative medicine.We review MSC-Exos and their therapeutic potential for a variety of diseases and injuries.

Modulation Effects of the 3D Strain Microenvironment on Characteristics of Mesenchymal Stem Cell-Derived Exosomes

It is necessary to investigate the characteristics of Mesenchymal stem cells(MSCs)derived exosomes,and especially their application in tissue regeneration.Previous studies have shown that inflammatory stimulation enhanced the secretion of MSC-derived exosomes with stronger anti-inflammatory protein,cytokine profiles,and functional RNA via altering COX2/PGE2 pathway.Recently,accumulating evidence has also revealed that biophysical cues(especially biomechanical cues)in cell microenvironment have significant effects not only on cells but also on their exosomes.It has been reported that applying bi-axial strain to MSCs induces formation of a stiffer cytoskeleton through mTORC2 signaling,which biases against adipogenic differentiation and toward osteoblastogenesis.At the same time,For example,dimensionality,composition and stiffness of the extracellular matrix(ECM)has been proved to affect the size and composition of exosomes secreted by cancer cells.However,the effects of biomechanical cues in the three-dimensional(3D)microenvironment on stem cell-derived exosomes remains to be unveiled.Therefore,it is important to understand the roles of 3D cell mechanical microenvironment in regulating the characteristics of stem cell-derived exosomes and develop more efficient approaches to enhance their functions.This study aimed to explore the changes in characteristics of exosomes secreted by MSCs in periodontium in response to the matrix strain in 3D.Periodontal ligament stem cells(PDLSCs)were cultured in a 3D strain microenvironment engineered with microscale magnetically stretched collagen hydrogels.The morphology,particle distribution,marker protein expression of PDLSC-derived exosomes were analyzed.Then the pro-osteogenic property of exosomes was evaluated by assessing cell viability,proliferation,migration and osteogenic differentiation of target cells,for instance human bone marrow mesenchymal stem cells(hBMSCs).Detailed characterizations revealed that PDLSC-derived exosomes in the 3D strain mi-croenvironment were with similar morphology,particle distribution and surface markers.Notably,Exosomes secreted by PDLSCs in strain microenvironment were more endocytosed by hBMSCs and were more potent in improving proliferation and migration of hBMSCs,comparing with PDLSCs in non-strain environment.Alizarin red staining and molecular biology experiments confirmed that treatment of exosomes secreted by PDLSCs under mechanical stimulation led to a significant increase in osteogenic differentiation of hBMSCs in vitro.Meanwhile,in vivo study also indicated that PDLSC-derived exosomes obtained from the 3D strain microenvironment could obviously promote new bone formation.Our findings revealed that mechanical cues profoundly affected the characteristics of PDLSC-derived exosomes,especially for their bio-activity,providing a foundation for using the 3D mechanical microenvironment to enhance the osteo-inductive functions of stem cell-derived exosomes in cell-free therapy for bone regeneration.

Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction?

Objective:The secretome,comprising bioactive chemicals released by mesenchymal stem cells(MSCs),holds therapeutic promise in regenerative medicine.This review aimed to explore the therapeutic potential of the MSC secretome in regenerative urology,particularly for treating erectile dysfunction(ED),and to provide an overview of preclinical and clinical research on MSCs in ED treatment and subsequently to highlight the rationales,mechanisms,preclinical investigations,and therapeutic potential of the MSC secretome in this context.Methods:The review incorporated an analysis of preclinical and clinical research involving MSCs in the treatment of ED.Subsequently,it delved into the existing knowledge regarding the MSC secretome,exploring its therapeutic potential.The methods included a comprehensive examination of relevant literature to discern the processes underlying the therapeutic efficacy of the MSC secretome.

Research Progresses in the Inhibitory Effect of Bone Mesenchymal Stem Cell-Derived Exosome on Blood-Brain Barrier Disruption following Intracerebral Hemorrhage in Rats

Mesenchymal Stem Cells (MSCs) are a type of non-hematopoietic progenitor cells which have self-replication capacity and multilineage differentiation. They have widely applied in studies of various diseases due to their effects in damaged tissue repair, neuroprotection and immunoregulation. MSCs can secret exosomes through multiple ways in the physiological or pathological state. Many researches’ results on MSC-Exo show that it possesses many functions similar to MSCs, such as immunoregulation and regeneration promotion of damaged tissues. Hence, MSC-Exo is believed to have considerable research potentials in regenerative medicines. This study reviewed the research progresses on biological characteristics and functions of MSC-Exo.

Therapeutic applications of exosomes from adipose-derived stem cells in antifibrosis

Fibrosis is a condition in which connective tissue replaces normal parenchymal tissue,resulting in significant tissue remodeling.Fibrosis can affect several organs and pose a serious threat to human health and life.Adiposederived stem cells(ASCs)have been suggested as promising candidates for antifibrotic therapies.Paracrine secretion is one of the key processes in stem cell therapy due to its critical function in cellular communication.ASC-derived exosomes(ASC-exos)are used as tools for restoring and regenerating damaged tissue,and they are now thought to orchestrate antifibrosis-related events.In this review,we summarize the recent findings and present an extensive view of the therapeutic applications of ASC-exos in fibrotic diseases.

BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway

Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes(BMSC-Exos)on PF in response to PD.Methods:Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing.C57BL/6J mice were infused with 4.25%glucose-based peritoneal dialysis fluid(PDF)for 6 consecutive weeks to establish a PF model.A total of 36 mice were randomly divided into 6 groups:control group,1.5%PDF group,2.5%PDF group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF.HE and Masson staining were performed to evaluate the extent of PF.The therapeutic potential of BMSC-Exos for PF was examined through pathological examination,RT-qPCR,Western blotting,and peritoneal function analyses.Epithelial-mesenchymal transition(EMT)of HMrSV5 was induced with 4.25%PDF.Cells were divided into control group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Cell Counting Kit-8 assay was used to measure cell viability,and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells.Results:Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs.The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos,but decreased in PD mice.We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice.Compared with the control mice,the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response,with markedly increased peritoneal thickness and higher expression ofα-SMA,collagen-I,fibronectin,and ECM1.The mice with PD showed decreased miR-27a-3p.Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment,while PF and mesothelial damage were significantly ameliorated.Additionally,markers of fibrosis(α-SMA,collagen-I,fibronectin,ECM1)and profibrotic cytokines(TGF-β1,PDGF)were downregulated at the mRNA and protein levels after BMSC-Exos treatment.In HMrSV5 cells,BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF.Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin(epithelial marker)and decreased expression ofα-SMA,Snail,and vimentin(mesenchymal markers)compared to those of the 4.25%PDF-treated cells.Importantly,a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p.TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos.Conclusion:The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.

Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment

The high incidence and disability rates of stroke pose a heavy burden on society.Inflammation is a significant pathological reaction that occurs after an ischemic stroke.Currently,therapeutic methods,except for intravenous thrombolysis and vascular thrombectomy,have limited time windows.Mesenchymal stem cells(MSCs)can migrate,differentiate,and inhibit inflammatory immune responses.Exosomes(Exos),which are secretory vesicles,have the characteristics of the cells from which they are derived,making them attractive targets for research in recent years.MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns.In this review,research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.

MicroRNA-451 from Human Umbilical Cord-Derived Mesenchymal Stem Cell Exosomes Inhibits Alveolar Macrophage Autophagy via Tuberous Sclerosis Complex 1/Mammalian Target of Rapamycin Pathway to Attenuate Burn-Induced Acute Lung Injury in Rats

Objective Our previous studies established that microRNA(miR)-451 from human umbilical cord mesenchymal stem cell-derived exosomes(hUC-MSC-Exos)alleviates acute lung injury(ALI).This study aims to elucidate the mechanisms by which miR-451 in hUC-MSC-Exos reduces ALI by modulating macrophage autophagy.Methods Exosomes were isolated from hUC-MSCs.Severe burn-induced ALI rat models were treated with hUC-MSC-Exos carrying the miR-451 inhibitor.Hematoxylin-eosin staining evaluated inflammatory injury.Enzyme-linked immunosorbnent assay measured lipopolysaccharide(LPS),tumor necrosis factor-α,and interleukin-1βlevels.qRT-PCR detected miR-451 and tuberous sclerosis complex 1(TSC1)expressions.The regulatory role of miR-451 on TSC1 was determined using a dual-luciferase reporter system.Western blotting determined TSC1 and proteins related to the mammalian target of rapamycin(mTOR)pathway and autophagy.Immunofluorescence analysis was conducted to examine exosomes phagocytosis in alveolar macrophages and autophagy level.Results hUC-MSC-Exos with miR-451 inhibitor reduced burn-induced ALI and promoted macrophage autophagy.MiR-451 could be transferred from hUC-MSCs to alveolar macrophages via exosomes and directly targeted TSC1.Inhibiting miR-451 in hUC-MSC-Exos elevated TSC1 expression and inactivated the mTOR pathway in alveolar macrophages.Silencing TSC1 activated mTOR signaling and inhibited autophagy,while TSC1 knockdown reversed the autophagy from the miR-451 inhibitor-induced.Conclusion miR-451 from hUC-MSC exosomes improves ALI by suppressing alveolar macrophage autophagy through modulation of the TSC1/mTOR pathway,providing a potential therapeutic strategy for ALI.

Exosomes from adipose tissue-derived stem/stromal cells:A key to future regenerative medicine

Advances in regenerative medicine correlate strongly with progress in the use of adipose tissue-derived mesenchymal stem/stromal cells.The range of therapeutic indications has also expanded over recent years.Numerous recent studies have highlighted the primary importance of paracrine secretion by these cells.Though it is interesting to compare the different types of such secretions,we believe that exosomes(extra-cellular vesicles possessing the same properties as their source cells)will likely be the main key in tomorrow’s cell therapy.Exosomes also have many advantages compared to the direct use of cells,making these particles amajor target in fundamental and translational research.

Effects of Adipose-derived Mesenchymal Stem Cell Exosomes on Corneal Stromal Fibroblast Viability and Extracellular Matrix Synthesis

Background： Corneal stromal cells （CSCs） are components of the corneal endothelial microenvironment that can be induced to form a functional tissue-engineered corneal endothelium. Adipose-derived mesenchymal stem cells （ADSCs） have been reported as an important component of regenerative medicine and cell therapy for corneal stromal damage. We have demonstrated that the treatment with ADSCs leads to phenotypic changes in CSCs in vitro. However, the underlying mechanisms of such ADSC-induced changes in CSCs remain unclear. Methods： ADSCs and CSCs were isolated from New Zealand white rabbits and cultured in vitro. An Exosome Isolation Kit, Western blotting, and nanoparticle tracking analysis （NTA） were used to isolate and confirm the exosomes from ADSC culture medium. Meanwhile, the optimal exosome concentration and treatment time were selected. Cell Counting Kit-8 and annexin V-fluorescein isothiocyanate/ propidium iodide assays were used to assess the effect of ADSC-derived exosomes on the proliferation and apoptosis of CSCs. To evaluate the effects ofADSC-derived exosomes on CSC invasion activity, Western blotting was used to detect the expression of matrix metalloproteinases （MMPs） and collagens. Results： ADSCs and CSCs were successfully isolated from New Zealand rabbits. The optimal concentration and treatment time of exosomes for the following study were 100 μg/ml and 96 h, respectively. NTA revealed that the ADSC-derived exosomes appeared as nanoparticles （40-200 nm）, and Western blotting confirmed positive expression of CD9, CDSI, flotillin-1, and HSP70 versus ADSC cytoplasmic proteins （all P〈 0.01 ）. ADSC-derived exosomes （50μg/ml and 100μg/ml） significantly promoted proliferation and inhibited apoptosis （mainly early apoptosis） of CSCs versus non-exosome-treated CSCs （all P 〈 0.05）. Interestingly, MMPs were downregulated and extracellular matrix （ECM）-related proteins including collagens and fibronectin were upregulated in the exosome-treated CSCs versus non-exosome-treated CSCs （MMPI： t = 80.103, P 〈 0.01; MMP2： t = 114.778, P 〈 0.01; MMP3： t = 56.208, P 〈 0.01; and MMP9： t = 60.617, P〈 0.01; collagen I： t = -82.742, P〈 0.01; collagen II： t = -72.818, P〈 0.01; collagen III： t = -104.452, P〈 0.01; collagen IV： t = - 133.426, P 〈 0.01, and collagen V： t - -294.019, P 〈 0.01 ; and fibronectin： t = -92.491, P 〈 0.01, respectively）. Conclusion： The findings indicate that ADSCs might play an important role in CSC viability regulation and ECM remodeling, partially through the secretion of exosomes.

Exosomes: Emerging implementation of nanotechnology for detecting and managing novel corona virus-SARS-CoV-2

The spread of SARS-CoV-2 as an emerging novel coronavirus disease (COVID-19) had progressed as a worldwide pandemic since the end of 2019. COVID-19 affects firstly lungs tissues which are known for their very slow regeneration. Afterwards, enormous cytokine stimulation occurs in the infected cells immediately after a lung infection which necessitates good management to save patients. Exosomes are extracellular vesicles of nanometric size released by reticulocytes on maturation and are known to mediate intercellular communications. The exosomal cargo serves as biomarkers in diagnosing various diseases;moreover, exosomes could be employed as nanocarriers in drug delivery systems. Exosomes look promising to combat the current pandemic since they contribute to the immune response against several viral pathogens. Many studies have proved the potential of using exosomes either as viral elements or host systems that acquire immune-stimulatory effects and could be used as a vaccine or drug delivery tool. It is essential to stop viral replication, prevent and reverse the massive storm of cytokine that worsens the infected patients’ situations for the management of COVID-19. The main benefits of exosomes could be;no cells will be introduced, no chance of mutation, lack of immunogenicity and the damaged genetic material that could negatively affect the recipient is avoided. Additionally, it was found that exosomes are static with no ability for in vivo reproduction. The current review article discusses the possibilities of using exosomes for detecting novel coronavirus and summarizes state of the art concerning the clinical trials initiated for examining the use of COVID-19 specific T cells derived exosomes and mesenchymal stem cells derived exosomes in managing COVID-19.

Exosomes derived from human adipose-derived stem cells ameliorate osteoporosis through miR-335-3p/Aplnr axis

Treatment of osteoporosis is still a challenge in clinic,which leads to an increasing social burden as the aging of population.Exosomes originated from human adipose-derived stem cells(hASCs)hold promise to promote osteogenic differentiation,thus may ameliorate osteoporosis.The main purpose of this study was to investigate the novel usage of hASC-derived exosomes in the treatment of osteoporosis and their underlying mechanism.Two types of exosomes,i.e.,exosomes derived from hASCs cultured in proliferation medium(P-Exos)and osteogenic induction medium(O-Exos),were obtained.As compared with P-Exos,O-Exos could promote the osteogenic differentiation of mouse bone marrow-derived stem cells(mBMSCs)from osteoporotic mice in vitro and ameliorated osteoporosis in vivo.Then,microRNA(miRNA)-335-3p was identified to be the key differentially expressed microRNA between the two exosomes by small RNA sequencing,gene overexpression and knock-down,qRT-PCR,and dual-luciferase reporter assay,and Aplnr was confirmed to be the potential target gene of miRNA-335-3p.In addition,miR335-3p inhibitor-optimized O-Exos were established by transfection of miR-335-3p inhibitor,which significantly enhanced the osteogenic differentiation of mBMSCs in vitro,and bone density and number of trabecular bones in vivo compared with unoptimized O-Exos.Our results indicated that the ASC-exosome-based therapy brings new possibilities for osteoporosis treatment.Besides,engineered exosomes based on transfection of miRNA are a promising strategy to optimize the therapeutic effect of exosomes on osteoporosis.

Mechanism, current status, and prospects of MSC and its extracellular vesicles in the treatment of IBD

The etiology of inflammatory bowel disease(IBD)is multifaceted,involving genetic susceptibility,immune dysregulation,alterations in the gut microbiota,and environmental factors.Both intrinsic and extrinsic factors can disrupt the intestinal mucosal barrier,leading to chronic nonspecific inflammation,local structural changes,and gastrointestinal dysfunction.Historically,due to a lack of effective treatments,recurrent inflammation and microcirculatory disturbances could result in complications such as intestinal fistulas,strictures,obstructions,perforations,gastrointestinal bleeding,sepsis,etc.,thereby increasing the risk of intestinal cell carcinoma and mortality.While the overall incidence of IBD remains at 0.5%in North America and Europe,its annual incidence is increasing in Asia,Africa,and South America,resulting in a growing number of patients and warning significant attention.Recent research has highlighted mesenchymal stem cell(MSC)therapy as an innovative treatment option for IBD due to its capacity to modulate inflammatory immune responses and promote tissue regeneration.A current preclinical study has shown a promising result,with systemic administration of MSCs in patients with reduced intestinal inflammation and no intestinal inflammation.In addition,in a new study,the use of mesenchymal stem cell-derived exosomes(MSC-EXOs)was successful,a type derived from mesenchymal stem cells,was successful,especially in patients with refractory anal fistula.Consequently,MSC therapy has become a preferred approach in IBD treatment,showcasing the potential application prospects for stem cell-based therapy in IBD.However,clinical research in this field still needs to refine strategies and further explore to lay a solid foundation.

Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission

Chronic diabetic wounds remain a globally recognized clinical challenge.They occur due to high concentrations of reactive oxygen species and vascular function disorders.A promising strategy for diabetic wound healing is the delivery of exosomes,comprising bioactive dressings.Metformin activates the vascular endothelial growth factor pathway,thereby improving angiogenesis in hyperglycemic states.However,multifunctional hydrogels loaded with drugs and bioactive substances synergistically promote wound repair has been rarely reported,and the mechanism of their combinatorial effect of exosome and metformin in wound healing remains unclear.Here,we engineered dual-loaded hydrogels possessing tissue adhesive,antioxidant,self-healing and electrical conductivity properties,wherein 4-armed SH-PEG cross-links with Ag^(+),which minimizes damage to the loaded goods and investigated their mechanism of promotion effect for wound repair.Multiwalled carbon nanotubes exhibiting good conductivity were also incorporated into the hydrogels to generate hydrogen bonds with the thiol group,creating a stable three-dimensional structure for exosome and metformin loading.The diabetic wound model of the present study suggests that the PEG/Ag/CNT-M+E hydrogel promotes wound healing by triggering cell proliferation and angiogenesis and relieving peritraumatic inflammation and vascular injury.The mechanism of the dual-loaded hydrogel involves reducing the level of reactive oxygen species by interfering with mitochondrial fission,thereby protecting F-actin homeostasis and alleviating microvascular dysfunction.Hence,we propose a drug-bioactive substance combination therapy and provide a potential mechanism for developing vascular function-associated strategies for treating chronic diabetic wounds.