Engineered-extracellular vesicles as an optimistic tool for microRNA delivery for osteoarthritis treatment

Esmaeili, Abazar; Hosseini, Samaneh; Eslaminejad, Mohamadreza Baghaban

doi:10.1007/s00018-020-03585-w

Cited by 29 publications

(21 citation statements)

References 97 publications

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“…Since isolating EVs based on their cellular origin is difficult, they are often characterized by their size upon purification with differential centrifugation and ultracentrifugation [ 11 ]. Since EVs can be edited and loaded with specific molecules which are then transported in a protected way, furthermore, EVs are efficiently taken up by target cells, they hold a great promise for cancer therapies as well [ 12 ]. However, molecules important in EV uptake and whether specific CRC subpopulations can be targeted by EVs more efficiently than others, are not yet known.…”

Section: Introductionmentioning

confidence: 99%

IFITM1 expression determines extracellular vesicle uptake in colorectal cancer

Kelemen

Carmi

Oszvald

et al. 2021

Cell. Mol. Life Sci.

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The majority of colorectal cancer (CRC) patients carry mutations in the APC gene, which lead to the unregulated activation of the Wnt pathway. Extracellular vesicles (EV) are considered potential therapeutic tools. Although CRC is a genetically heterogeneous disease, the significance of the intra-tumor heterogeneity in EV uptake of CRC cells is not yet known. By using mouse and patient-derived organoids, the currently available best model of capturing cellular heterogeneity, we found that Apc mutation induced the expression of interferon-induced transmembrane protein 1 (Ifitm1), a membrane protein that plays a major role in cellular antiviral responses. Importantly, organoids derived from IFITM1high CRC cells contained more proliferating cells and they had a markedly reduced uptake of fibroblast EVs as compared to IFITM1low/− cells. In contrast, there was no difference in the intensity of EV release between CRC subpopulations with high and low IFITM1 levels. Importantly, the difference in cell proliferation between these two subpopulations disappeared in the presence of fibroblast-derived EVs, proving the functional relevance of the enhanced EV uptake by IFITM1low CRC cells. Furthermore, inactivating IFITM1 resulted in an enhanced EV uptake, highlighting the importance of this molecule in establishing the cellular difference for EV effects. Collectively, we identified CRC cells with functional difference in their EV uptake ability that must be taken into consideration when using EVs as therapeutic tools for targeting cancer cells.

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Section: Introductionmentioning

confidence: 99%

IFITM1 expression determines extracellular vesicle uptake in colorectal cancer

Kelemen

Carmi

Oszvald

et al. 2021

Cell. Mol. Life Sci.

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“…While endogenous MSCs and chondrocytes were found to be successfully recruited for meniscus regeneration in animal models, no disease-modifying treatment is available to regenerate human menisci [ 41 ]. EV transplantation may orchestrate cellular processes, such as migration, cell growth, and matrix synthesis, which are associated with tissue regeneration [ 39 , 42 ]. Previous studies have shown that EVs can increase the cell growth and migration of chondrocytes and regenerate cartilage in the proteomic avascular joint resembling the meniscus [ 21 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles derived from mesenchymal stromal cells mediate endogenous cell growth and migration via the CXCL5 and CXCL6/CXCR2 axes and repair menisci

et al. 2021

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Background Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are promising candidates for tissue regeneration therapy. However, the therapeutic efficacy of MSC-EVs for meniscus regeneration is uncertain, and the mechanisms underlying MSC-EV-mediated tissue regeneration have not been fully elucidated. The aims of this study were to evaluate the therapeutic efficacy of intra-articular MSC-EV injection in a meniscus defect model and elucidate the mechanism underlying MSC-EV-mediated tissue regeneration via combined bioinformatic analyses. Methods MSC-EVs were isolated from human synovial MSC culture supernatants via ultrafiltration. To evaluate the meniscus regeneration ability, MSC-EVs were injected intra-articularly in the mouse meniscus defect model immediately after meniscus resection and weekly thereafter. After 1 and 3 weeks, their knees were excised for histological and immunohistochemical evaluations. To investigate the mechanisms through which MSC-EVs accelerate meniscus regeneration, cell growth, migration, and chondrogenesis assays were performed using treated and untreated chondrocytes and synovial MSCs with or without MSC-EVs. RNA sequencing assessed the gene expression profile of chondrocytes stimulated by MSC-EVs. Antagonists of the human chemokine CXCR2 receptor (SB265610) were used to determine the role of CXCR2 on chondrocyte cell growth and migration induced by MSC-EVs. Results In the meniscus defect model, MSC-EV injection accelerated meniscus regeneration and normalized the morphology and composition of the repaired tissue. MSC-EVs stimulated chondrocyte and synovial MSC cell growth and migration. RNA sequencing revealed that MSC-EVs induced 168 differentially expressed genes in the chondrocytes and significantly upregulated CXCL5 and CXCL6 in chondrocytes and synovial MSCs. Suppression of CXCL5 and CXCL6 and antagonism of the CXCR2 receptor binding CXCL5 and CXCL6 negated the influence of MSC-EVs on chondrocyte cell growth and migration. Conclusions Intra-articular MSC-EV administration repaired meniscus defects and augmented chondrocyte and synovial MSC cell growth and migration. Comprehensive transcriptome/RNA sequencing data confirmed that MSC-EVs upregulated CXCL5 and CXCL6 in chondrocytes and mediated the cell growth and migration of these cells via the CXCR2 axis.

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“…In summary, several miRNAs are known to be associated with different processes relevant to OD ( 169 ), such as inflammation (miR-22, miR-320) ( 105 , 110 ), extracellular matrix synthesis (miR-148a, miR-27, miR-218) ( 170 , 171 ) and chondrocyte proliferation. Additionally, several miRNAs have been shown to be involved in processes associated with MSCs differentiation into chondrocytes (miR-19a, miR-410) ( 172 , 173 ), and processes such as chondrocyte hypertrophy (miR-381, miR-140) ( 174 , 175 ), apoptosis and autophagy (miR-30b) ( 176 ) ( Table 1 ).…”

Section: Mirna Shuttled By Sevs Derived From Mscs and Their Therapeutic Function On Osteoarticular Diseasesmentioning

confidence: 99%

Role of microRNA Shuttled in Small Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells for Osteoarticular Disease Treatment

et al. 2021

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Osteoarticular diseases (OD), such as rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic autoimmune/inflammatory and age-related diseases that affect the joints and other organs for which the current therapies are not effective. Cell therapy using mesenchymal stem/stromal cells (MSCs) is an alternative treatment due to their immunomodulatory and tissue differentiation capacity. Several experimental studies in numerous diseases have demonstrated the MSCs’ therapeutic effects. However, MSCs have shown heterogeneity, instability of stemness and differentiation capacities, limited homing ability, and various adverse responses such as abnormal differentiation and tumor formation. Recently, acellular therapy based on MSC secreted factors has raised the attention of several studies. It has been shown that molecules embedded in extracellular vesicles (EVs) derived from MSCs, particularly those from the small fraction enriched in exosomes (sEVs), effectively mimic their impact in target cells. The biological effects of sEVs critically depend on their cargo, where sEVs-embedded microRNAs (miRNAs) are particularly relevant due to their crucial role in gene expression regulation. Therefore, in this review, we will focus on the effect of sEVs derived from MSCs and their miRNA cargo on target cells associated with the pathology of RA and OA and their potential therapeutic impact.

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Engineered-extracellular vesicles as an optimistic tool for microRNA delivery for osteoarthritis treatment

Cited by 29 publications

References 97 publications

IFITM1 expression determines extracellular vesicle uptake in colorectal cancer

IFITM1 expression determines extracellular vesicle uptake in colorectal cancer

Extracellular vesicles derived from mesenchymal stromal cells mediate endogenous cell growth and migration via the CXCL5 and CXCL6/CXCR2 axes and repair menisci

Role of microRNA Shuttled in Small Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells for Osteoarticular Disease Treatment

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