Browsing by Subject "Exosomes"

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    Biodistribution of Modified Extracellular Vesicles In Normal and Tumor-Bearing Animal Models
    (2020-06) Alshareef, Duha
    Exosomes are one of the extracellular vesicles (EVs) that range in diameter from 30-150 nm. They are formed by early budding into early endosomes then released by the cell from late endosome. The content of EVs includes proteins, mRNA, miRNA, and DNA derived from the original cell where they were released. Due to the membrane structure of EVs, which resemble the original cell, and the ability to alter the EVs cargo, EVs are extensively studied as an approach for the development of drug delivery system and as immunotherapy. miR-424/322 is a microRNA that present in some tumor-derived EVs and plays a role in regulating anti-tumor immune response. Our lab has shown that modified EVs with miR-424/322 blockade prevented the initiation of tumor in colorectal cancer (CRC) animal model through inducing the antitumor immune response. One of the critical aspects of using EVs as a therapy and/or a drug delivery system is to understand their biodistribution in vivo. In this thesis, we systemically injected modified EVs labeled with the lipophilic dye DiO to both normal and orthotopic-tumor animal models. We harvested the following tissues: blood, heart, lung, spleen, liver, kidney, lymph nodes, bone marrow, GI, muscle, and tumor 30 min post-injection and analyzed their single-cell suspension preparations using flow cytometry analysis. Our data showed that EVs are mainly distributed to the lung, liver and spleen in naïve animals. For tumor-bearing animals more data is required to determine the potential difference between the two groups. In conclusion, EVs administered intravenously to the animal generally followed the biodistribution pattern of previously published studies that used the same rout of injection.
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    Role of Schwann cell-derived Exosomes in Cisplatin-induced Hyperalgesia
    (2018-05) Kim, Amy
    Painful peripheral neuropathy is a common dose-limiting side effect associated with cisplatin treatment. Cisplatin is unable to cross the blood-brain barrier, and its neurotoxicity is limited to the peripheral nervous system (PNS). In the PNS, Schwann cells are an essential component supporting dorsal root ganglion (DRG) neuron viability, and impairments in Schwann cell biology contribute to cisplatin-induced painful neuropathy. We explored the role of Schwann cell-derived exosomes in the development of cisplatin-induced hyperalgesia. Consistent with our previous reports, daily injection of cisplatin (1 mg/kg, i.p.) for 7 days produced mechanical hyperalgesia in C3H/HeN mice. To investigate the impact of exosome signaling in the development of cisplatin-induced hyperalgesia, exosomes isolated from the sciatic nerves of cisplatin-treated mice were injected intrathecally into naïve mice for 5 consecutive days (7 g of total protein/10 l, i.t.). Mechanical hyperalgesia was observed after the second injection of exosomes, mimicking the effect of cisplatin alone and supporting the involvement of integrated exosome signaling in hyperalgesia produced by cisplatin. Intrathecal administration of Schwann cell-derived exosomes activated microglia, and analysis of exosomal content indicated mediators of neuronal sensitization at the central level. Collectively, our results indicate that Schwann cells affected by cisplatin contribute to mechanical hyperalgesia and exosomes are an important signaling mediator for glia-neuronal communication.