BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression.
Ontology highlight
ABSTRACT:
SUBMITTER: Roccaro AM
PROVIDER: S-EPMC3613927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mesenchymal stromal/stem cells (MSCs) are widely utilized in cell therapy because of their robust immunomodulatory and regenerative properties. Their paracrine activity is one of the most important features that contribute to their efficacy. Recently, it has been demonstrated that the production of various factors via extracellular vesicles, especially exosomes, governs the principal efficacy of MSCs after infusion in experimental models. Compared to MSCs themselves, MSC-derived exosomes (MSC-Exos) have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities. MSC-Exos is becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of MSC-Exos in different diseases. In this review, we summarized the ongoing and completed clinical studies using MSC-Exos for immunomodulation, regenerative medicine, gene delivery, and beyond. Additionally, we summarized MSC-Exos production methods utilized in these studies with an emphasis on MSCs source, MSC-Exos isolation methods, characterization, dosage, and route of administration. Lastly, we discussed the current challenges and future directions of exosome utilization in different clinical studies as a novel therapeutic strategy.
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Project description:Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient's sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes.
| S-EPMC4537049 | biostudies-literature
Project description:In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann-Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.
| S-EPMC7464474 | biostudies-literature
Project description:Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.
| S-EPMC7290908 | biostudies-literature
Project description:Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.
| S-EPMC5116561 | biostudies-literature
Project description:Background: Bone marrow mesenchymal stem cells (bmMSC) may play a role in the regulation of maturation, proliferation, and functional activation of lymphocytes, though the exact mechanisms are unknown. MSC-derived exosomes induce a regulatory response in the function of B, T, and monocyte-derived dendritic cells. Here, we evaluated the specific inhibition of human lymphocytes by bmMSC-derived exosomes and the effects on B-cell function. Methods: Exosomes were isolated from culture media of bmMSC obtained from several healthy donors. The effect of purified bmMSC-derived exosomes on activated peripheral blood mononuclear cells (PBMCs) and isolated B and T lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester assay. Using the Illumina sequencing platform, mRNA profiling was performed on B-lymphocytes activated in the presence or absence of exosomes. Ingenuity® pathway analysis software was applied to analyze pathway networks, and biological functions of the differentially expressed genes. Validation by RT-PCR was performed. The effect of bmMSC-derived exosomes on antibody secretion was measured by ELISA. Results: Proliferation of activated PBMCs or isolated T and B cells co-cultured with MSC-derived exosomes decreased by 37, 23, and 18%, respectively, compared to controls. mRNA profiling of activated B-lymphocytes revealed 186 genes that were differentially expressed between exosome-treated and control cells. We observed down- and up-regulation of genes that are involved in cell trafficking, development, hemostasis, and immune cell function. RNA-Seq results were validated by real time PCR analysis for the expression of CXCL8 (IL8) and MZB1 genes that are known to have an important role in immune modulation. Functional alterations were confirmed by decreased IgM production levels. Consistent results were demonstrated among a wide variety of healthy human bmMSC donors. Conclusion: Our data show that exosomes may play an important role in immune regulation. They inhibit proliferation of several types of immune cells. In B-lymphocytes they modulate cell function by exerting differential expression of the mRNA of relevant genes. The results of this study help elucidate the mechanisms by which exosomes induce immune regulation and may contribute to the development of newer and safer therapeutic strategies.
| S-EPMC6308164 | biostudies-literature
Project description:Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Through exosomes, mesenchymal stem cells confer chemoresistance to MM cells, while myeloma cells promote angiogenesis, influence immune response, cause bone lesions, and have an impact on the outcome of MM patients. In this review, we analyze the role played by exosomes in the progression of monoclonal gammopathies and the effects on the proliferation of neoplastic plasma cells, and discuss the possible employment of exosomes as potential targets for the treatment of MM patients.
| S-EPMC8616233 | biostudies-literature
Project description:Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.
| S-EPMC4131274 | biostudies-literature
Project description: Not available
| S-EPMC7212470 | biostudies-literature
Project description:Aims/hypothesisDiabetic peripheral neuropathy (DPN) is one of the major complications of diabetes, which contributes greatly to morbidity and mortality. There is currently no effective treatment for this disease. Exosomes are cell-derived nanovesicles and play an important role in intercellular communications. The present study investigated whether mesenchymal stromal cell (MSC)-derived exosomes improve neurological outcomes of DPN.MethodsExosomes were isolated from the medium of cultured mouse MSCs by ultracentrifugation. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at the age of 20 weeks were used as DPN models. Heterozygous mice (db/m) of the same age were used as the control. MSC-exosomes were administered weekly via the tail vein for 8 weeks. Neurological function was evaluated by testing motor and sensory nerve conduction velocities, and thermal and mechanical sensitivity. Morphometric analysis was performed by myelin sheath staining and immunohistochemistry. Macrophage markers and circulating cytokines were measured by western blot and ELISA. MicroRNA (miRNA) array and bioinformatics analyses were performed to examine the exosomal miRNA profile and miRNA putative target genes involved in DPN.ResultsTreatment of DPN with MSC-exosomes markedly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity in diabetic mice. Histopathological analysis showed that MSC-exosomes markedly augmented the density of FITC-dextran perfused blood vessels and increased the number of intraepidermal nerve fibres (IENFs), myelin thickness and axonal diameters of sciatic nerves. Western blot analysis revealed that MSC-exosome treatment decreased and increased M1 and M2 macrophage phenotype markers, respectively. Moreover, MSC-exosomes substantially suppressed proinflammatory cytokines. Bioinformatics analysis revealed that MSC-exosomes contained abundant miRNAs that target the Toll-like receptor (TLR)4/NF-κB signalling pathway.Conclusions/interpretationMSC-derived exosomes alleviate neurovascular dysfunction and improve functional recovery in mice with DPN by suppression of proinflammatory genes.
| S-EPMC6949414 | biostudies-literature