Cell-free therapy based on extracellular vesicles: a promising therapeutic strategy for peripheral nerve injury.

Peripheral nerve injury (PNI) is one of the public health concerns that can result in a loss of sensory or motor function in the areas in which injured and non-injured nerves come together. Up until now, there has been no optimized therapy for complete nerve regeneration after PNI. Exosome-based therapies are an emerging and effective therapeutic strategy for promoting nerve regeneration and functional recovery. Exosomes, as natural extracellular vesicles, contain bioactive molecules for intracellular communications and nervous tissue function, which could overcome the challenges of cell-based therapies. Furthermore, the bioactivity and ability of exosomes to deliver various types of agents, such as proteins and microRNA, have made exosomes a potential approach for neurotherapeutics. However, the type of cell origin, dosage, and targeted delivery of exosomes still pose challenges for the clinical translation of exosome therapeutics. In this review, we have focused on Schwann cell and mesenchymal stem cell (MSC)-derived exosomes in nerve tissue regeneration. Also, we expressed the current understanding of MSC-derived exosomes related to nerve regeneration and provided insights for developing a cell-free MSC therapeutic strategy for nerve injury.

Angiogenesis and Its Targeting in Glioblastoma with Focus on Clinical Approaches.

Angiogenesis is a characteristic of glioblastoma (GBM), the most fatal and therapeutic-resistant brain tumor. Highly expressed angiogenic cytokines and proliferated microvascular system made anti-angiogenesis treatments a thoroughly plausible approach for GBM treatment. Many trials have proved to be not only as a safe but also as an effective approach in GBM retardation in a certain time window as seen in radiographic response rates; however, they have failed to implement significant improvements in clinical manifestation whether alone or in combination with radio/chemotherapy. Bevasizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, is the only agent that exerts meaningful clinical influence by improving progression-free survival (PFS) and partially alleviate clinical symptoms, nevertheless, it could not prolong the overall survival (OS) in patients with GBM. The data generated from phase II trials clearly revealed a correlation between elevated reperfusion, subsequent to vascular normalization induction, and improved clinical outcomes which explicitly indicates anti-angiogenesis treatments are beneficial. In order to prolong these initial benefits observed in a certain period of time after anti-angiogenesis targeting, some aspects of the therapy should be tackled: recognition of other bypass angiogenesis pathways activated following antiangiogenesis therapy, identification of probable pathways that induce insensitivity to shortage of blood supply, and classifying the patients by mapping their GBM-related gene profile as biomarkers to predict their responsiveness to therapy. Herein, the molecular basis of brain vasculature development in normal and tumoral conditions is briefly discussed and it is explained how "vascular normalization" concept opened a window to a better comprehension of some adverse effects observed in anti-angiogenesis therapy in clinical condition. Then, the most targeted angiogenesis pathways focused on ligand/receptor interactions in GBM clinical trials are reviewed. Lastly, different targeting strategies applied in anti-angiogenesis treatment are discussed.

Targeting TRAF3IP2 inhibits angiogenesis in glioblastoma.

Increased vascularization, also known as neoangiogenesis, plays a major role in many cancers, including glioblastoma multiforme (GBM), by contributing to their aggressive growth and metastasis. Although anti-angiogenic therapies provide some clinical improvement, they fail to significantly improve the overall survival of GBM patients. Since various pro-angiogenic mediators drive GBM, we hypothesized that identifying targetable genes that broadly inhibit multiple pro-angiogenic mediators will significantly promote favorable outcomes. Here, we identified TRAF3IP2 (TRAF3-interacting protein 2) as a critical regulator of angiogenesis in GBM. We demonstrated that knockdown of TRAF3IP2 in an intracranial model of GBM significantly reduces vascularization. Targeting TRAF3IP2 significantly downregulated VEGF, IL6, ANGPT2, IL8, FZGF2, PGF, IL1ß, EGF, PDGFRB, and VEGFR2 expression in residual tumors. Our data also indicate that exogenous addition of VEGF partially restores angiogenesis by TRAF3IP2-silenced cells, suggesting that TRAF3IP2 promotes angiogenesis through VEGF- and non-VEGF-dependent mechanisms. These results indicate the anti-angiogenic and anti-tumorigenic potential of targeting TRAF3IP2 in GBM, a deadly cancer with limited treatment options.

TRAF3IP2, a novel therapeutic target in glioblastoma multiforme.

Glioblastoma multiforme (glioblastoma) remains one of the deadliest cancers. Pro-inflammatory and pro-tumorigenic mediators present in tumor microenvironment (TME) facilitate communication between tumor cells and adjacent non-malignant cells, resulting in glioblastoma growth. Since a majority of these mediators are products of NF-κB- and/or AP-1-responsive genes, and as TRAF3 Interacting Protein 2 (TRAF3IP2) is an upstream regulator of both transcription factors, we hypothesized that targeting TRAF3IP2 blunts tumor growth by inhibiting NF-κB and pro-inflammatory/pro-tumorigenic mediators. Our in vitro data demonstrate that similar to primary glioblastoma tumor tissues, malignant glioblastoma cell lines (U87 and U118) express high levels of TRAF3IP2. Silencing TRAF3IP2 expression inhibits basal and inducible NF-κB activation, induction of pro-inflammatory mediators, clusters of genes involved in cell cycle progression and angiogenesis, and formation of spheroids. Additionally, silencing TRAF3IP2 significantly increases apoptosis. In vivo studies indicate TRAF3IP2-silenced U87 cells formed smaller tumors. Additionally, treating existing tumors formed by wild type U87 cells with lentiviral TRAF3IP2 shRNA markedly regresses their size. Analysis of residual tumors revealed reduced expression of pro-inflammatory/pro-tumorigenic/pro-angiogenic mediators and kinesins. In contrast, the expression of IL-10, an anti-inflammatory cytokine, was increased. Together, these novel data indicate that TRAF3IP2 is a master regulator of malignant signaling in glioblastoma, and its targeting modulates the TME and inhibits tumor growth by suppressing the expression of mediators involved in inflammation, angiogenesis, growth, and malignant transformation. Our data identify TRAF3IP2 as a potential therapeutic target in glioblastoma growth and dissemination.

The extracellular vesicles-derived from mesenchymal stromal cells: A new therapeutic option in regenerative medicine.

Mesenchymal stem cells (MSCs) are adult multipotent cells that due to their ability to homing to damaged tissues and differentiate into specialized cells, are remarkable cells in the field of regenerative medicine. It's suggested that the predominant mechanism of MSCs in tissue repair might be related to their paracrine activity. The utilization of MSCs for tissue repair is initially based on the differentiation ability of these cells; however now it has been revealed that only a small fraction of the transplanted MSCs actually fuse and survive in host tissues. Indeed, MSCs supply the microenvironment with the secretion of soluble trophic factors, survival signals and the release of extracellular vesicles (EVs) such as exosome. Also, the paracrine activity of EVs could mediate the cellular communication to induce cell-differentiation/self-renewal. Recent findings suggest that EVs released by MSCs may also be critical in the physiological function of these cells. This review provides an overview of MSC-derived extracellular vesicles as a hopeful opportunity to advance novel cell-free therapy strategies that might prevail over the obstacles and risks associated with the use of native or engineered stem cells. EVs are very stable; they can pass the biological barriers without rejection and can shuttle bioactive molecules from one cell to another, causing the exchange of genetic information and reprogramming of the recipient cells. Moreover, extracellular vesicles may provide therapeutic cargo for a wide range of diseases and cancer therapy.