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1.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575956

RESUMO

Umbilical cord blood (UCB) has long been seen as a rich source of naïve cells with strong regenerative potential, likely mediated by paracrine signals. More recently, small extracellular vesicles (sEV), such as exosomes, have been shown to play essential roles in cell-to-cell communication, via the transport of numerous molecules, including small RNAs. Often explored for their potential as biomarkers, sEV are now known to have regenerative and immunomodulating characteristics, particularly if isolated from stem cell-rich tissues. In this study, we aim to characterize the immunomodulating properties of umbilical cord blood mononuclear cell-derived sEV (UCB-MNC-sEV) and explore their therapeutic potential for inflammatory skin diseases. UCB-MNC-sEV were shown to shift macrophages toward an anti-inflammatory phenotype, which in turn exert paracrine effects on fibroblasts, despite previous inflammatory stimuli. Additionally, the incubation of PBMC with UCB-MNC-sEV resulted in a reduction of total CD4+ and CD8+ T-cell proliferation and cytokine release, while specifically supporting the development of regulatory T-cells (Treg), by influencing FOXP3 expression. In a 3D model of psoriatic skin, UCB-MNC-sEV reduced the expression of inflammatory and psoriatic markers IL6, IL8, CXCL10, COX2, S100A7, and DEFB4. In vivo, UCB-MNC-sEV significantly prevented or reversed acanthosis in imiquimod-induced psoriasis, and tendentially increased the number of Treg in skin, without having an overall impact on disease burden. This work provides evidence for the anti-inflammatory and tolerogenic effect of UCB-MNC-sEV, which may be harnessed for the treatment of Th17-driven inflammatory skin diseases, such as psoriasis.


Assuntos
Exossomos/imunologia , Fatores de Transcrição Forkhead/genética , Imunomodulação/imunologia , Inflamação/terapia , Psoríase/terapia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Proliferação de Células/genética , Citocinas/genética , Exossomos/genética , Exossomos/transplante , Vesículas Extracelulares/transplante , Feminino , Sangue Fetal/imunologia , Sangue Fetal/transplante , Humanos , Imunomodulação/genética , Inflamação/sangue , Inflamação/patologia , Macrófagos/imunologia , Masculino , Comunicação Parácrina/genética , Comunicação Parácrina/imunologia , Psoríase/sangue , Psoríase/patologia , Linfócitos T Reguladores/imunologia
2.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445251

RESUMO

Exosomes secreted by adipose-derived stem cells (ADSC-exo) reportedly improve nerve regeneration after peripheral nerve injury. Herein, we investigated whether pretreatment of ADSCs with FK506, an immunosuppressive drug that enhances nerve regeneration, could secret exosomes (ADSC-F-exo) that further augment nerve regeneration. Designed exosomes were topically applied to injured nerve in a mouse model of sciatic nerve crush injury to assess the nerve regeneration efficacy. Outcomes were determined by histomorphometric analysis of semi-thin nerve sections stained with toluidine blue, mouse neurogenesis PCR array, and neurotrophin expression in distal nerve segments. Isobaric tags for relative and absolute quantitation (iTRAQ) were used to profile potential exosomal proteins facilitating nerve regeneration. We observed that locally applied ADSC-exo and ADSC-F-exo significantly enhanced nerve regeneration after nerve crush injury. Pretreatment of ADSCs with FK506 failed to produce exosomes possessing more potent molecules for enhanced nerve regeneration. Proteomic analysis revealed that of 192 exosomal proteins detected in both ADSC-exo and ADSC-F-exo, histone deacetylases (HDACs), amyloid-beta A4 protein (APP), and integrin beta-1 (ITGB1) might be involved in enhancing nerve regeneration.


Assuntos
Tecido Adiposo/metabolismo , Exossomos , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/terapia , Nervos Periféricos/fisiologia , Células-Tronco/metabolismo , Tacrolimo/farmacologia , Animais , Exossomos/metabolismo , Exossomos/transplante , Camundongos , Traumatismos dos Nervos Periféricos/metabolismo
3.
Arch Biochem Biophys ; 710: 109002, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352243

RESUMO

Osteoarthritis (OA) is the most common painful disease with chronic articular cartilage degeneration. The pathological process of OA is complex and characterized by the imbalance between the synthesis and catabolism of chondrocytes and extracellular matrix, leading to the progressive destruction of articular cartilage damage. Because of the self-renewal and differentiation of mesenchymal stem cells (MSCs), various exogenous MSC-based cell therapies have been developed to treat OA. Moreover, the efficacy of MSC- based therapy is mainly attributed to the paracrine of cytokines, growth factors, and exosomes. Exosomes derived from MSCs can deliver various DNAs, RNAs, proteins and lipids, thus promoting MSCs migration and cartilage repair. Therefore, MSC-derived exosomes are considered as a promising alternative therapy for OA. In this review, we summarized properties of MSC-derived exosomes and the new role of MSC-derived exosomes in the treatment of OA. We also proposed possible perspectives of MSC-derived exosomes as cell-free regenerative reagents in the treatment of OA.


Assuntos
Exossomos/metabolismo , Exossomos/transplante , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/metabolismo , Osteoartrite/terapia , Animais , Materiais Biocompatíveis/uso terapêutico , Cartilagem Articular/metabolismo , Diferenciação Celular , Proliferação de Células , Terapia Baseada em Transplante de Células e Tecidos/métodos , Sistema Livre de Células , Condrócitos/metabolismo , Exossomos/genética , Matriz Extracelular/metabolismo , Técnicas Genéticas , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Medicina Regenerativa/métodos
4.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360616

RESUMO

Acute respiratory distress syndrome (ARDS) represents a current challenge for medicine due to its incidence, morbidity and mortality and, also, the absence of an optimal treatment. The COVID-19 outbreak only increased the urgent demand for an affordable, safe and effective treatment for this process. Early clinical trials suggest the therapeutic usefulness of mesenchymal stem cells (MSCs) in acute lung injury (ALI) and ARDS. MSC-based therapies show antimicrobial, anti-inflammatory, regenerative, angiogenic, antifibrotic, anti-oxidative stress and anti-apoptotic actions, which can thwart the physiopathological mechanisms engaged in ARDS. In addition, MSC secretome and their derived products, especially exosomes, may reproduce the therapeutic effects of MSC in lung injury. This last strategy of treatment could avoid several safety issues potentially associated with the transplantation of living and proliferative cell populations and may be formulated in different forms. However, the following diverse limitations must be addressed: (i) selection of the optimal MSC, bearing in mind both the heterogeneity among donors and across different histological origins, (ii) massive obtention of these biological products through genetic manipulations of the most appropriate MSC, (iii) bioreactors that allow their growth in 3D, (iv) ideal culture conditions and (v) adequate functional testing of these obtaining biological products before their clinical application.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Transplante de Células-Tronco Mesenquimais/tendências , Células-Tronco Mesenquimais/fisiologia , Síndrome do Desconforto Respiratório/terapia , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/terapia , COVID-19/complicações , COVID-19/terapia , Exossomos/transplante , Humanos , Células-Tronco Mesenquimais/química , Síndrome do Desconforto Respiratório/etiologia
5.
Biomolecules ; 11(6)2021 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199330

RESUMO

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Bancos de Espécimes Biológicos , Exossomos , Células-Tronco/metabolismo , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Exossomos/metabolismo , Exossomos/transplante , Humanos , MicroRNAs/metabolismo , Células-Tronco/citologia
6.
Front Immunol ; 12: 634138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220800

RESUMO

Schistosomiasis is a parasitic disease endemic to freshwater areas of Southeast Asia, Africa, and South America that is capable of causing serious damage to the internal organs. Recent studies have linked exosomes to the progression of schistosomiasis. These structures are important mediators for intercellular communication, assist cells to exchange proteins, lipids, and genetic material and have been shown to play critical roles during host-parasite interactions. This review aims to discuss the pathophysiology of exosomes in schistosomiasis and their roles in regulating the host immune response. Understanding how exosomes are involved in the pathogenesis of schistosomiasis may provide new perspectives in diagnosing and treating this neglected disease.


Assuntos
Exossomos/parasitologia , Schistosoma/patogenicidade , Esquistossomose/parasitologia , Animais , Exossomos/imunologia , Exossomos/metabolismo , Exossomos/transplante , Interações Hospedeiro-Patógeno , Humanos , Prognóstico , Vacinas Protozoárias/uso terapêutico , Schistosoma/efeitos dos fármacos , Schistosoma/imunologia , Esquistossomose/imunologia , Esquistossomose/metabolismo , Esquistossomose/prevenção & controle , Esquistossomicidas/uso terapêutico , Transdução de Sinais
7.
Cell Death Dis ; 12(7): 695, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257272

RESUMO

Exosomes derived from tumor cells play a key role in tumor development. In the present study, we identified the bioactivity of exosomes released from WERI-Rb1 retinoblastoma cells in tumor angiogenesis, as well as the underlying mechanism, through biochemical methods and animal experiments. Our in vitro data showed that exosomes could be engulfed by human vesicle endothelial cells (HUVECs), significantly promote cell viability and induce an inflammatory response in HUVECs by increasing the expression of a series of related genes, such as IL-1, IL-6, IL-8, MCP-1, VCAM1, and ICAM1. Significant increases in migration and tube formation were also observed in the HUVECs incubated with exosomes. Moreover, experiments with a nude mouse xenotransplantation model showed that exosomes injected near tumors could be strongly absorbed by tumor cells. The numbers of endothelial cells and blood vessels were significantly increased in tumor tissues treated with exosomes compared to control tissues. Furthermore, to reveal the mechanism underlying exosome-mediated angiogenesis in retinoblastoma, we analyzed the levels of 12 microRNAs in the exosomes. Specifically, our data showed that miR-92a-3p was enriched in RB exosomes. Accordingly, miR-92a-3p was increased in the HUVECs incubated with these exosomes. After treatment with a miR-92a-3p inhibitor, the promoting effect of exosomes on the migration and tube formation of HUVECs was significantly abrogated. The expression of the angiogenesis-related genes mentioned above was markedly decreased in HUVECs. Similarly, treatment with a microRNA mimic also demonstrated that miR-92a-3p was involved in the angiogenesis of HUVECs. More importantly, bioinformatics analysis predicted that Krüppel-like factor 2 (KLF2), a member of the KLF family of zinc-finger transcription factors, might be an active target of miR-92a-3p. Notably, this prediction was confirmed both in vitro and in vivo. Thus, our work suggests that exosomal miR-92a-3p is involved in tumor angiogenesis and might be a promising therapeutic candidate for retinoblastoma.


Assuntos
Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/metabolismo , Neovascularização Patológica , Neovascularização Fisiológica , Comunicação Parácrina , Neoplasias da Retina/metabolismo , Retinoblastoma/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Exossomos/genética , Exossomos/patologia , Exossomos/transplante , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Nus , MicroRNAs/genética , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Retinoblastoma/genética , Retinoblastoma/patologia
8.
Cell Death Dis ; 12(7): 662, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215717

RESUMO

Bone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-ß/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-ß/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.


Assuntos
Neoplasias Ósseas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Exossomos/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Osteoclastos/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Células A549 , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Exossomos/genética , Exossomos/transplante , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neuropeptídeos , Osteoclastos/patologia , Células RAW 264.7 , RNA Longo não Codificante/genética , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/genética
9.
Cell Prolif ; 54(8): e13093, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34231932

RESUMO

OBJECTIVES: The study aimed to determine whether dental pulp stem cell-derived exosomes (DPSC-Exos) exert protective effects against cerebral ischaemia-reperfusion (I/R) injury and explore its underlying mechanism. MATERIALS AND METHODS: Exosomes were isolated from the culture medium of human DPSC. Adult male C57BL/6 mice were subjected to 2 hours transient middle cerebral artery occlusion (tMCAO) injury followed by 2 hours reperfusion, after which singular injection of DPSC-Exos via tail vein was administrated. Brain oedema, cerebral infarction and neurological impairment were measured on day 7 after exosomes injection. Then, oxygen-glucose deprivation-reperfusion (OGD/R) induced BV2 cells were studied to analyse the therapeutic effects of DPSC-Exos on I/R injury in vitro. Protein levels of TLR4, MyD88, NF-κB p65, HMGB1, IL-6, IL-1ß and TNF-α were determined by western blot or enzyme-linked immunosorbent assay. The cytoplasmic translocation of HMGB1 was detected by immunofluorescence staining. RESULTS: DPSC-Exos alleviated brain oedema, cerebral infarction and neurological impairment in I/R mice. DPSC-Exos inhibited the I/R-mediated expression of TLR4, MyD88 and NF-κB significantly. DPSC-Exos also reduced the protein expression of IL-6, IL-1ß and TNF-α compared with those of the control both in vitro and in vivo. Meanwhile, DPSC-Exos markedly decreased the HMGB1 cytoplasmic translocation induced by I/R damage. CONCLUSIONS: DPSC-Exos can ameliorate I/R-induced cerebral injury in mice. Its anti-inflammatory mechanism might be related with the inhibition of the HMGB1/TLR4/MyD88/NF-κB pathway.


Assuntos
Citocinas/metabolismo , Exossomos/transplante , Traumatismo por Reperfusão/terapia , Animais , Sobrevivência Celular , Citoplasma/metabolismo , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Modelos Animais de Doenças , Exossomos/metabolismo , Proteína HMGB1/metabolismo , Inflamação/metabolismo , Inflamação/terapia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Traumatismo por Reperfusão/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo
10.
Biomed Pharmacother ; 138: 111529, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311529

RESUMO

Hepatocellular carcinoma (HCC) has become a challenging disease in the world today. Due to the limitations on the current diagnosis and treatment as well as its high metastatic ability and high recurrence rate, HCC gradually becomes the second deadliest tumor. Exosomes are one of the types of cell-derived vesicles and can carry intracellular materials such as genetic materials, lipids, and proteins. In recent years, it has been verified that exosomes are linked to numerous physiological and pathological processes, including HCC. However, how exosomes affect HCC progression remains largely unknown. In this review, the exosome-mediated cellular material transfer between cells of different types in the HCC microenvironment and their effects on the behaviors and functions of recipient cells are studied. Furthermore, we also addressed the underlying molecular mechanisms. We believe that new light on the diagnosis of this cancer as well as its treatment strategies will be shed after a collation of literature in this area.


Assuntos
Carcinoma Hepatocelular/metabolismo , Comunicação Celular , Exossomos/metabolismo , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Portadores de Fármacos , Exossomos/genética , Exossomos/patologia , Exossomos/transplante , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Valor Preditivo dos Testes , Transdução de Sinais
11.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206364

RESUMO

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.


Assuntos
Doenças Cocleares/etiologia , Doenças Cocleares/terapia , Exossomos/metabolismo , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/citologia , Animais , Antineoplásicos/efeitos adversos , Terapia Biológica , Biomarcadores , Cisplatino/efeitos adversos , Doenças Cocleares/patologia , Modelos Animais de Doenças , Exossomos/transplante , Células Ciliadas Auditivas Externas/patologia , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Perda Auditiva/terapia , Imunofenotipagem , Camundongos , MicroRNAs/genética , Proteômica/métodos , Resultado do Tratamento
12.
Cell Death Dis ; 12(7): 628, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145224

RESUMO

With an increasing aging society, China is the world's fastest growing markets for oral implants. Compared with traditional oral implants, immediate implants cause marginal bone resorption and increase the failure rate of osseointegration, but the mechanism is still unknown. Therefore, it is important to further study mechanisms of tension stimulus on osteoblasts and osteoclasts at the early stage of osseointegration to promote rapid osseointegration around oral implants. The results showed that exosomes containing circ_0008542 from MC3T3-E1 cells with prolonged tensile stimulation promoted osteoclast differentiation and bone resorption. Circ_0008542 upregulated Tnfrsf11a (RANK) gene expression by acting as a miR-185-5p sponge. Meanwhile, the circ_0008542 1916-1992 bp segment exhibited increased m6A methylation levels. Inhibiting the RNA methyltransferase METTL3 or overexpressing the RNA demethylase ALKBH5 reversed osteoclast differentiation and bone resorption induced by circ_0008542. Injection of circ_0008542 + ALKBH5 into the tail vein of mice reversed the same effects in vivo. Site-directed mutagenesis study demonstrated that 1956 bp on circ_0008542 is the m6A functional site with the abovementioned biological functions. In conclusion, the RNA methylase METTL3 acts on the m6A functional site of 1956 bp in circ_0008542, promoting competitive binding of miRNA-185-5p by circ_0008542, and leading to an increase in the target gene RANK and the initiation of osteoclast bone absorption. In contrast, the RNA demethylase ALKBH5 inhibits the binding of circ_0008542 with miRNA-185-5p to correct the bone resorption process. The potential value of this study provides methods to enhance the resistance of immediate implants through use of exosomes releasing ALKBH5.


Assuntos
Reabsorção Óssea/metabolismo , Comunicação Celular , Diferenciação Celular , Exossomos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , RNA Circular/metabolismo , Células 3T3 , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Microambiente Celular , Exossomos/transplante , Feminino , Mecanotransdução Celular , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Osseointegração , Osteoblastos/transplante , Osteoclastos/patologia , Células RAW 264.7 , RNA Circular/genética , Ratos , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Estresse Mecânico
13.
Cell Prolif ; 54(7): e13074, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34101281

RESUMO

OBJECTIVES: Pulp regeneration brings big challenges for clinicians, and vascularization is considered as its determining factor. We previously accomplished pulp regeneration with autologous stem cells from deciduous teeth (SHED) aggregates implantation in teenager patients, however, the underlying mechanism needs to be clarified for regenerating pulp in adults. Serving as an important effector of mesenchymal stem cells (MSCs), exosomes have been reported to promote angiogenesis and tissue regeneration effectively. Here, we aimed to investigate the role of SHED aggregate-derived exosomes (SA-Exo) in the angiogenesis of pulp regeneration. MATERIALS AND METHODS: We extracted exosomes from SHED aggregates and utilized them in the pulp regeneration animal model. The pro-angiogenetic effects of SA-Exo on SHED and human umbilical vein endothelial cells (HUVECs) were evaluated. The related mechanisms were further investigated. RESULTS: We firstly found that SA-Exo significantly improved pulp tissue regeneration and angiogenesis in vivo. Next, we found that SA-Exo promoted SHED endothelial differentiation and enhanced the angiogenic ability of HUVECs, as indicated by the in vitro tube formation assay. Mechanistically, miR-26a, which is enriched in SA-Exo, improved angiogenesis both in SHED and HUVECs via regulating TGF-ß/SMAD2/3 signalling. CONCLUSIONS: In summary, these data reveal that SA-Exo shuttled miR-26a promotes angiogenesis via TGF-ß/SMAD2/3 signalling contributing to SHED aggregate-based pulp tissue regeneration. These novel insights into SA-Exo may facilitate the development of new strategies for pulp regeneration.


Assuntos
Polpa Dentária/fisiologia , Exossomos/metabolismo , MicroRNAs/metabolismo , Neovascularização Fisiológica , Transdução de Sinais , Compostos de Anilina/farmacologia , Antagomirs/metabolismo , Compostos de Benzilideno/farmacologia , Diferenciação Celular/efeitos dos fármacos , Exossomos/transplante , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Dente Decíduo/citologia , Fator de Crescimento Transformador beta/metabolismo
14.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071399

RESUMO

Extracellular vesicles (EVs) have been described as important mediators of cell communication, regulating several physiological processes, including tissue recovery and regeneration. In the kidneys, EVs derived from stem cells have been shown to support tissue recovery in diverse disease models and have been considered an interesting alternative to cell therapy. For this purpose, however, several challenges remain to be overcome, such as the requirement of a high number of EVs for human therapy and the need for optimization of techniques for their isolation and characterization. Moreover, the kidney's complexity and the pathological process to be treated require that EVs present a heterogeneous group of molecules to be delivered. In this review, we discuss the recent advances in the use of EVs as a therapeutic tool for kidney diseases. Moreover, we give an overview of the new technologies applied to improve EVs' efficacy, such as novel methods of EV production and isolation by means of bioreactors and microfluidics, bioengineering the EV content and the use of alternative cell sources, including kidney organoids, to support their transfer to clinical applications.


Assuntos
Injúria Renal Aguda/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Insuficiência Renal Crônica/terapia , Bioengenharia/métodos , Técnicas de Cultura de Células/métodos , Exossomos/transplante , Vesículas Extracelulares/transplante , Humanos , Células-Tronco Mesenquimais/citologia , Tamanho da Partícula
15.
J Biomed Sci ; 28(1): 39, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34030679

RESUMO

Mesenchymal stem cells (MSCs) have been demonstrated to have a great potential in the treatment of several diseases due to their differentiation and immunomodulatory capabilities and their ability to be easily cultured and manipulated. Recent investigations revealed that their therapeutic effect is largely mediated by the secretion of paracrine factors including exosomes. Exosomes reflect biophysical features of MSCs and are considered more effective than MSCs themselves. Alternative approaches based on MSC-derived exosomes can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy. Furthermore, MSC-derived exosomes may provide a potent therapeutic strategy for various diseases and are promising candidates for cell-based and cell-free regenerative medicine. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our current knowledge about exosomes: their biogenesis and molecular composition, and how they exert their effects on target cells. Particularly, the therapeutic potential of MSC-derived exosomes in experimental models and recent clinical trials to evaluate their safety and efficacy are summarized in this study. Overall, this paper provides a current overview of exosomes as a new cell-free therapeutic agent.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Exossomos/transplante , Transplante de Células-Tronco Mesenquimais/estatística & dados numéricos , Medicina Regenerativa/estatística & dados numéricos , Diferenciação Celular , Humanos , Imunomodulação
16.
Aging (Albany NY) ; 13(11): 15032-15043, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031267

RESUMO

BACKGROUND: Human amniotic epithelial cells (hAECs) are seed cells used to treat acute myocardial infarction (AMI), but their mechanism remains unclear. METHODS: We cultured hAECs and extracted exosomes from culture supernatants. Next, we established a stable AMI model in rats and treated them with hAECs, exosomes, or PBS. We assess cardiac function after treatment by echocardiography. Additionally, heart tissues were collected and analyzed by Masson's trichrome staining. We conducted the tube formation and apoptosis assays to explore the potential mechanisms. RESULTS: Cardiac function was improved, and tissue fibrosis was decreased following implantation of hAECs and their exosomes. Echocardiography showed that the EF and FS were lower in the control group than in the hAEC and exosome groups, and that the LVEDD and LVESD were higher in the control group (P<0.05). Masson's trichrome staining showed that the fibrotic area was larger in the control group. Tube formation was more efficient in the hAEC and exosome groups (P<0.0001). Additionally, the apoptosis rates of myocardial cells in the hAEC and exosome groups were significantly decreased (P<0.0001). CONCLUSIONS: hAECs and their exosomes improved the cardiac function of rats after AMI by promoting angiogenesis and reducing the apoptosis of cardiac myocytes.


Assuntos
Âmnio/citologia , Células Epiteliais/metabolismo , Células Epiteliais/transplante , Exossomos/transplante , Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Eletrocardiografia , Exossomos/metabolismo , Exossomos/ultraestrutura , Fibrose , Humanos , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Miócitos Cardíacos , Ratos Sprague-Dawley
17.
Front Immunol ; 12: 628973, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868247

RESUMO

Exosomes are cell-derived nanovesicles carrying protein, lipid, and nucleic acid for secreting cells, and act as significant signal transport vectors for cell-cell communication and immune modulation. Immune-cell-derived exosomes have been found to contain molecules involved in immunological pathways, such as MHCII, cytokines, and pathogenic antigens. Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the most fatal infectious diseases. The pathogen for tuberculosis escapes the immune defense and continues to replicate despite rigorous and complicate host cell mechanisms. The infected-cell-derived exosomes under this circumstance are found to trigger different immune responses, such as inflammation, antigen presentation, and activate subsequent pathways, highlighting the critical role of exosomes in anti-MTB immune response. Additionally, as a novel kind of delivery system, exosomes show potential in developing new vaccination and treatment of tuberculosis. We here summarize recent research progress regarding exosomes in the immune environment during MTB infection, and further discuss the potential of exosomes as delivery system for novel anti-MTB vaccines and therapies.


Assuntos
Exossomos/transplante , Imunoterapia , Mycobacterium tuberculosis/patogenicidade , Vacinas contra a Tuberculose/uso terapêutico , Tuberculose/terapia , Imunidade Adaptativa , Animais , Autofagia , Exossomos/imunologia , Exossomos/microbiologia , Humanos , Evasão da Resposta Imune , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia
18.
J Mater Chem B ; 9(18): 3800-3807, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33899897

RESUMO

Osteogenesis and angiogenesis are both important for implant osseointegration, which can be tailored by immunomodulation of macrophages. Zn, a novel biodegradable material, can modulate macrophage functions in its ionic form. However, whether macrophage-derived exosomes, novel carriers of intracellular communication, participate in the process is still unclear. The present work shows that Zn ions in the concentration range of 0-100 µM have no significant influence on macrophage viability, proliferation, morphology, and secretion amount of exosomes, but generally downregulate the gene expression of both M1 and M2 markers. The exosomes can be ingested continuously by osteoblasts and endothelial cells. The osteoblasts show the highest alkaline phosphatase activity after ingesting the exosomes derived from macrophages upon 4 µM Zn ion stimulation. In contrast, the endothelial cells migrate the furthest distance after ingesting the exosomes upon 20 µM Zn ion stimulation. These results indicate that Zn ions may vary the composition of macrophage-derived exosomes, which in turn affects the osteogenesis and angiogenesis. These findings are meaningful for the surface design of immunomodulatory biomaterials from the perspective of macrophage-derived exosomes.


Assuntos
Movimento Celular/efeitos dos fármacos , Exossomos/metabolismo , Regulação para Cima/efeitos dos fármacos , Zinco/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Exossomos/efeitos dos fármacos , Exossomos/transplante , Íons/química , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microscopia de Fluorescência , Osteoblastos/citologia , Osteoblastos/metabolismo , Células RAW 264.7 , Zinco/química
19.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808241

RESUMO

Around 40% of the population will suffer at some point in their life a disease involving tissue loss or an inflammatory or autoimmune process that cannot be satisfactorily controlled with current therapies. An alternative for these processes is represented by stem cells and, especially, mesenchymal stem cells (MSC). Numerous preclinical studies have shown MSC to have therapeutic effects in different clinical conditions, probably due to their mesodermal origin. Thereby, MSC appear to play a central role in the control of a galaxy of intercellular signals of anti-inflammatory, regenerative, angiogenic, anti-fibrotic, anti-oxidative stress effects of anti-apoptotic, anti-tumor, or anti-microbial type. This concept forces us to return to the origin of natural physiological processes as a starting point to understand the evolution of MSC therapy in the field of regenerative medicine. These biological effects, demonstrated in countless preclinical studies, justify their first clinical applications, and draw a horizon of new therapeutic strategies. However, several limitations of MSC as cell therapy are recognized, such as safety issues, handling difficulties for therapeutic purposes, and high economic cost. For these reasons, there is an ongoing tendency to consider the use of MSC-derived secretome products as a therapeutic tool, since they reproduce the effects of their parent cells. However, it will be necessary to resolve key aspects, such as the choice of the ideal type of MSC according to their origin for each therapeutic indication and the implementation of new standardized production strategies. Therefore, stem cell science based on an intelligently designed production of MSC and or their derivative products will be able to advance towards an innovative and more personalized medical biotechnology.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Transplante de Células-Tronco Mesenquimais/tendências , Células-Tronco Mesenquimais/metabolismo , Animais , Exossomos/metabolismo , Exossomos/transplante , Humanos , Medicina Regenerativa/métodos , Medicina Regenerativa/tendências
20.
Oncol Rep ; 45(3): 809-823, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650640

RESUMO

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges for the treatment of HCC is the prevention or management of recurrence and metastasis of HCC. It has been found that chemokines and their receptors serve a pivotal role in HCC progression. In the present review, the literature on the multifactorial roles of exosomes in HCC from PubMed, Cochrane library and Embase were obtained, with a specific focus on the functions and mechanisms of chemokines in HCC. To date, >50 chemokines have been found, which can be divided into four families: CXC, CX3C, CC and XC, according to the different positions of the conserved N­terminal cysteine residues. Chemokines are involved in the inflammatory response, tumor immune response, proliferation, invasion and metastasis via modulation of various signaling pathways. Thus, chemokines and their receptors directly or indirectly shape the tumor cell microenvironment, and regulate the biological behavior of the tumor. In addition, the potential application of chemokines in chemotaxis of exosomes as drug vehicles is discussed. Exosomes containing chemokines or expressing receptors for chemokines may improve chemotaxis to HCC and may thus be exploited for targeted drug delivery.


Assuntos
Carcinoma Hepatocelular/metabolismo , Quimiocinas/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Quimiocinas/uso terapêutico , Progressão da Doença , Exossomos/metabolismo , Exossomos/transplante , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/uso terapêutico , Transdução de Sinais , Microambiente Tumoral
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