Fischell Department of Bioengineering Research Works

Permanent URI for this collectionhttp://hdl.handle.net/1903/6627

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Author: search.filters.author.Levy, DanielSubject: search.filters.subject.inflammation

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    Combinatorial microRNA Loading into Extracellular Vesicles for Increased Anti-Inflammatory Efficacy
    (MDPI, 2022-10-21) Pottash, Alex Eli; Levy, Daniel; Jeyaram, Anjana; Kuo, Leo; Kronstadt, Stephanie M.; Chao, Wei; Jay, Steven M.
    Extracellular vesicles (EVs) have emerged as promising therapeutic entities in part due to their potential to regulate multiple signaling pathways in target cells. This potential is derived from the broad array of constituent and/or cargo molecules associated with EVs. Among these, microRNAs (miRNAs) are commonly implicated as important and have been associated with a wide variety of EV-induced biological phenomena. While controlled loading of single miRNAs is a well-documented approach for enhancing EV bioactivity, loading of multiple miRNAs has not been fully leveraged to maximize the potential of EV-based therapies. Here, an established approach to extrinsic nucleic acid loading of EVs, sonication, was utilized to load multiple miRNAs in HEK293T EVs. Combinations of miRNAs were compared to single miRNAs with respect to anti-inflammatory outcomes in assays of increasing stringency, with the combination of miR-146a, miR-155, and miR-223 found to have the most potential amongst the tested groups.
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    Induced Pluripotent Stem Cell-Derived Extracellular Vesicles Promote Wound Repair in a Diabetic Mouse Model via an Anti-Inflammatory Immunomodulatory Mechanism
    (Wiley, 2023-06-19) Levy, Daniel; Abadchi, Sanaz Nourhammadi; Shababi, Niloufar; Ravari, Mohsen Rouhani; Pirolli, Nicholas H.; Bergeron, Cade; Obiorah, Angel; Mokhtari-Esbuie, Farzad; Gheshlaghi, Shayan; Abraham, John M.; Smith, Ian M.; Powsner, Emily H.; Solomon, Talia J.; Harmon, John W.; Jay, Steven M.
    Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have recently been explored in clinical trials for treatment of diseases with complex pathophysiologies. However, production of MSC EVs is currently hampered by donor-specific characteristics and limited ex vivo expansion capabilities before decreased potency, thus restricting their potential as a scalable and reproducible therapeutic. Induced pluripotent stem cells (iPSCs) represent a self-renewing source for obtaining differentiated iPSC-derived MSCs (iMSCs), circumventing both scalability and donor variability concerns for therapeutic EV production. Thus, it is initially sought to evaluate the therapeutic potential of iMSC EVs. Interestingly, while utilizing undifferentiated iPSC EVs as a control, it is found that their vascularization bioactivity is similar and their anti-inflammatory bioactivity is superior to donor-matched iMSC EVs in cell-based assays. To supplement this initial in vitro bioactivity screen, a diabetic wound healing mouse model where both the pro-vascularization and anti-inflammatory activity of these EVs would be beneficial is employed. In this in vivo model, iPSC EVs more effectively mediate inflammation resolution within the wound bed. Combined with the lack of additional differentiation steps required for iMSC generation, these results support the use of undifferentiated iPSCs as a source for therapeutic EV production with respect to both scalability and efficacy.