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| Category | Source of EVs | Type of EVs | Disease | Experimental settings | Findings | Ref |
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| Normal MSC-EV-based therapy | BM-MSCs from healthy donors and MM patients | Exosomes | MM | Mice were administrated with MM cells (MM.1S cell line) and exosomes from normal BM-MSCs or MM BM-MCSs. Next, differences in the exosomes content from the two sources were sought. | Unlike MM BM-MCS-exosomes, normal BM-MSC-exosomes inhibited the growth and metastasis of MM cells in mice. Normal BM-MSC-exosomes had low levels of IL6, CCL2, and fibronectin and high levels of 15a miR compared with MM BM-MSC-exosomes | [49] |
| Normal MSC-EV-based therapy | BM-MSCs from healthy donors and MM patients | MVs | MM | Normal or MM BM-MSC-MVs were in vitro incubated with MM cells (cell lines: U266, ARP1, MM1S, OPM2, and RPMI 8226). Next, the crosstalk between the MVs and MM cells was studied. | Normal BM-MSC-MVs inhibited the growth, survival, and migration of MM cells. In contrast to MVs from MM BM-MSCs, these from normal BM-MSC limited expression and/or phosphorylation of MAPKs (ERK1/2 and JNK), translation initiation (TI) factors (eIF4GI and eIF4E), TI regulator (TOR, MNK1/2 and 4EBP), and oncogenes (NFκB, SMAD5, cyclin D, HIF1α, cMyc) in MM cells | [50] |
| Normal MSC-EVs-based therapy | BM-MSCs from healthy young and old donors | Exosomes | MM | Mice were inoculated with MM cells and BM-MSC-exosomes | MM-induced angiogenesis was strongly inhibited by BM-MSC-exosomes from young donors compared with that from old donors | [54] |
| Normal MSC-EV-based therapy | BM-MSCs from healthy donors and MDS patients | EVs | MDS | BM-MSC-EVs were in vitro incubated with hematopoietic progenitor cells CD34+. | Increased survival and clongeneity of hematopoietic progenitor were observed postincubation with BM-MSC-EVs from MDS patients but not healthy donors. Unlike MDS BM-MSC-EVs, these from healthy donors did not increase the expression of miR10a and miR 15a, which are implicated in the development of MDS, in the hematopoietic progenitor. | [56] |
| Normal MSC-EV-based therapy | BM-MSCs from healthy donors and AML patients | Exosomes | AML | BM-MSC-exosomes were in vitro incubated with AML cells. | In contrast to exosomes from AML patients, exosomes of healthy donors sensitized AML cells to chemotherapy (FLT3 inhibitor). | [60] |
| Normal MSC-EV-based therapy | BM-MSCs from healthy donors | EVs | Allo-HSCT-induced GVHD | BM-MSC-EVs were in vitro incubated with UCHSCs. Next, the transcriptome of UCHSCs was characterized postincubation. The BM-MSC-EV content of miRs was also sequenced. In mice, UCHSCs with or without BM-MSC-EVs were injected. | In vitro, BM-MSC-EVs supported the viability and restricted the differentiation of UCHSCs. Postincubation, UCHSCs increased the expression of genes involved in cell movement and growth and reduced expression of genes implicated in apoptosis. The EVs enclosed miRs whose target genes in UCHSCs were reduced implying a mechanism of action. Coadministration of UCHSCs with BM-MSC-EVs in mice augmented the engraftment of UCHSCs. | [75] |
| Normal MSC-EV-based therapy | BM-MSCs from healthy donors | Exosomes | Allo-HSCT-induced acute GVHD | Proinflammatory and anti-inflammatory cytokines were measured in BM-MSC-exosomes derived from four donors. The most potent source was selected for administration into patient with steroid-resistant acute GVHD postallo-HSCT. Proinflammatory cytokines of the patient’s PBMCs were measured following administration of BM-MSC-exosomes. | BM-MSC-exosomes were found to carry reduced levels of proinflammatory cytokines (IL6, IL17a, IL21, TNF-a, IFN-g) and high levels of anti- inflammatory molecules (IL10, TGF beta, and HLAG). The immunomodulatory potential of the BM-MSC-exosomes differed significantly between the donors. The administration of BM-MSC-exosomes into the patient reduced the production of proinflammatory cytokines from PBMCs and improved the symptoms of GVHD. | [80] |
| Normal MSC-EVs-based therapy | BM-MSCs and NHDFs from healthy donors | Exosomes | Acute GVHD | Exosomes from BM-MSCs and NHDFs were administrated into mice with acute GVHD. Next, cellular immune response was studied. Exosomal content of miRs was also characterized. | Only exosomes from BM-MSCs were able to ameliorate the symptoms of GVHD. BM-MSC-exosomes suppressed T-helper cells and T-cytotoxic cells. In contrast to exosomes from NHDFs, these from BM-MSCs enclosed higher levels of miRs that target genes implicated in cellular proliferation, TCR signaling and GVHD. | [76] |
| Normal MSC-EV-based therapy | UC-MSC from healthy donors | EVs | Allo-HSCT-induced acute GVHD | UC-MSC-EVs were injected into a mouse model of allo-HSCT with acute GVHD. Next, the immune response in mice was studied. | UC-MSC-EVs alleviated the burden of acute GVHD and increased the survival rate of recipient mice. The serum levels of IL-2, TNF-α, and IFN-γ dropped postinjection with UC-MSC-EVs. In contrast, the level of IL10 in serum and the ration of Th-cells/T-cytotoxic cells were increased. | [77] |
| Normal MSC-EV-based therapy | BM-MSCs and fibroblasts from healthy donors | Exosomes | Chronic GVHD | Exosomes from BM-MSCs or fibroblasts were inoculated into mice with chronic GVHD. Next, the immune response in mice was studied. | Improvement of GVHD symptoms was possible only postinjection with BM-MSC-exosomes. The activation, migration, and infiltration of CD4 T-cells were inhibited by BM-MSC-exosomes but not fibroblast-exosomes. BM-MSC-exosomes also reduced the production of proinflammatory cytokines (IL-17A, IL-21, IL-22, and IL-2) in PBMCs of mice. | [78] |
| Exosome-based vaccine | AML cells (NP4 cell line) | Exosomes | AML | AML cell exosomes were in vitro incorporated into pulsed dendritic cells (DC). The DCs were then incubated with T-lymphocytes (CTLs). Next, CTLs as effector cells were in vitro incubated with AML cells. | CTLs became immunized against AML cells postincubation with DCs, in which AML cell exosomes were internalized. CTLs confer cytotoxicity against AML cells. | [82] |
| Exosome-based vaccine | CML cells (K562 cell line) | Exosomes | CML | In vitro pulsed DCs uptook CML cell exosomes. CTLs were incubated with the DCs. Next, CML cells were treated with the CTLs in vitro and in vivo. | DCs incorporating CML cell-exosome-induced immunity of CTLs that caused death of CML cells in vitro. The administration of the DCs to mice protected them from developing CML postinoculation with CML cells. | [83] |
| Exosome-based vaccine | LL cells (L1210 cell line) | Exosomes | LL | Exosomes from LL cells that lack or express TGF-β1 were independently internalized by DCs. Next, DCs were injected into mice. The mice were then inoculated with LL cells. | The DCs incorporated with exosomes lacking the expression of TGF-β1 conferred stronger protection against LL compared with DCs that uptook TGF-β1 expressing exosomes. | [87] |
| Targeting EVs | BM-MSCs (HS-5 cell line) | EVs | AML and CML | FGFR was inhibited (or gene silenced) in BM-MSCs (HS-5 cell line). Next, the BM-MSCs were in vitro incubated with AML and CML cells (MOLM14 and K562 cell lines). The leukemic cells were also administrated to Fgf2 -/- and Fgf2 +/+ mice. | Targeting FGFR inhibited the release of exosomes from BM-MSC, which abolished the protective impact of the BM-MSCs on the leukemia cells. Mice lacking the expression of FGF2 survived longer than those that that expressed FGF2. | [89] |
| Targeting EVs | Lymphoma cells (EL4 cell line) | Exosomes | Lymphoma | Mice were injected with lymphoma cells (EL4 cell line). Then, they were treated with cyclophosphamide with or without DMA. | DMA inhibited exosomes release in vivo. Furthermore, the combination of cyclophosphamide with DMA significantly reduced the tumor growth, while cyclophosphamide alone had a little effect on the tumor growth. | [90] |
| Targeting EVs | MM cell lines (RPMI8226, H929, MM1S and U266) | Exosomes | MM | Exosomes from MM cell lines (RPMI8226, H929, MM1S and U266) with or without endocytosis inhibitor (heparin) were incubated with BM-MSCs. | In the absence of heparin, MM cell exosomes were internalized by BM-MSCs, which reprogrammed the latter to support the MM growth. Heparin inhibited the uptake of MM cell exosomes by BM-MScs; hence, the tumor-supportive impact of BM-MSCs was abolished. | [92] |
| Targeting EVs | AML stem cells | Exosomes | AML | AML stem cells were transfected with miR-34c-5p mimic, and the proliferation of AML cells was assayed. Mice were transplanted with AML cells. Three weeks later, the mice were treated with miR-34c-5p agomir. | In vitro, the increased expression miR-34c- blocked the release of exosomes from AML stem cells. In vivo miR-34c-p-dependent blockage of exosomes shedding antagonized the growth of AML in mice. | [93] |
| Targeting EVs | B-cell lymphoma primary cells and cell lines (Su-DHL-4, Balm-3, OCI-Ly1). | Exosomes | B-cell lymphoma | Surface expression of CD20 was measured on exosomes from B-cell lymphoma primary cells and cell lines (Su-DHL-4, Balm-3, OCI-Ly1). These exosomes were in vitro incubated with known concentration of anti-CD20 antibody (rituximab). Plasma from patients receiving rituximab was also incubated with the exosomes. B-cell lymphoma cells were treated with inhibitor of exosome release and then were treated with rituximab. | B-cell lymphoma cells express high level of surface CD20, which bound to rituximab, protecting the malignant cells from the cytolytic effect of the drug. Inhibition of exosomes release form B-cell lymphoma cells sensitized them to rituximab. | [94] |
| EVs for drug delivery | Embryonic kidney cells (HEK293T-cell line) | Exosomes | CML | HEK293T cell were forced to express surface IL3 and were treated with a kinase inhibitor (Imatinib) or BCR-ABL siRNA. Next, Exosomes with the surface expression of IL3 that contained imatinib or BCR-ABL siRNA were isolated and applied to imatinib-resistant CML blast (LAMA84 and K562 cell lines) in vitro. The engineered exosomes were also injected into mice that were previously inoculated with CML blasts. | The engineered exosomes selectively inhibited the growth of CML in vitro and in vivo. The distribution analysis of the engineered exosomes in vivo showed that they accumulated at the tumor site. | [102] |
| EVs for drug delivery | Embryonic kidney cells (HEK293T-cell line) | Exosomes | CML | HEK293T cells were transfected to with plasmid of BFP-miR-21 sponge-MS2. Exosomes released from the engineered HEK293T cells were isolated and modified to carry aptamer AS1411 on their surface. The engineered exosomes were applied in vitro to CML blasts (K562 cell line). | The exosomes were u-taken by the CML blast, and miR-21 sponge-MS2 was delivered, leading to apoptosis induction in the malignant cells. Aptamer AS1411 enhanced the ability of the exosomes to target CML blasts. | [103] |
| EVs for drug delivery | Embryonic kidney cells (HEK293T-cell line) | Exosomes | CML | Exosomes released from HEK293T cells were isolated, alkalinized, and exogenously loaded with miR328. The exosomes were used for the treatment of imatinib-resistant CML blasts (K562 cell line). | The endocytosis of the exosomes into imatinib-resistant CML blasts sensitized the later to imatinib. | [106] |
| EVs for drug delivery | Fibroblasts (NIH3T3 cell line) | Exosomes | Lymphoma | Exosomes from NIH3T3 cells were either endogenously or exogenously loaded with siRNA of c-myc. Next, lymphoma cells with an overexpression of c-myc were treated with the exosomes. | The delivery of the exosomes into lymphoma cells reduced the expression of c-myc and inhibited the growth of lymphoma. | [107] |
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