作者: Mithieux, Suzanne M ; Liu, Linyang ; Wang, Yiwei ; Shi, Huaikai ; Hawkett, Brian S ; Wang, Ziyu ; Wong, Wai Cheng ; Weiss, Anthony S ; Silveira, Pablo A ; Pham, Nguyen T H

Wound healing is facilitated by biomaterials-based grafts and substantially impacted by orchestrated inflammatory responses that are essential to the normal repair process. Tropoelastin (TE) based materials are known to shorten the period for wound repair but the mechanism of anti-inflammatory performance is not known. To explore this, we compared the performance of the gold standard Integra Dermal Regeneration Template (Integra), polyglycerol sebacate (PGS), and TE blended with PGS, in a murine full-thickness cutaneous wound healing study. Systemically, blending with TE favorably increased the F4/80⁺ macrophage population by day 7 in the spleen and contemporaneously induced elevated plasma levels of anti-inflammatory IL-10. In contrast, the PGS graft without TE prompted prolonged inflammation, as evidenced by splenomegaly and greater splenic granulocyte and monocyte fractions at day 14. Locally, the inclusion of TE in the graft led to increased anti-inflammatory M2 macrophages and CD4⁺T cells at the wound site, and a rise in Foxp3⁺ regulatory T cells in the wound bed by day 7. We conclude that the TE-incorporated skin graft delivers a pro-healing environment by modulating systemic and local tissue responses. STATEMENT OF SIGNIFICANCE: Tropoelastin (TE) has shown significant benefits in promoting the repair and regeneration of damaged human tissues. In this study, we show that TE promotes an anti-inflammatory environment that facilitates cutaneous wound healing. In a mouse model, we find that inserting a TE-containing material into a full-thickness wound results in defined, pro-healing local and systemic tissue responses. These findings advance our understanding of TE's restorative value in tissue engineering and regenerative medicine, and pave the way for clinical applications.

2024-03-01·Biochimica et Biophysica Acta (BBA) - General Subjects

Engineered extracellular vesicles expressing ICAM-1: A promising targeted delivery system for T cell modifications

Article

作者: Farahani, Mahboube Shahrabi ; Hosseini-Beheshti, Elham ; Moazzeni, Seyed Mohammad ; Moghadam, Mehdi Forouzandeh

BACKGROUNDExtracellular vesicles (EVs) are natural nano-carriers that possess the required crucial features of an ideal biomolecular delivery system. However, using unmodified EVs may have some limitations such as low accumulation in target sites. Studies have established that engineering EVs against different cell surface markers can overcome most of these hurdles.METHODSIn this study, engineered EVs expressing ICAM-1/LAMP2b fusion protein on their surfaces were produced and isolated. The uptake of isolated targeted and non-targeted EVs was evaluated by imaging and flow cytometry. To assess the ability of targeted EVs to be applied as a safe carrier, pAAVS1-Puro-GFP plasmids were encapsulated into EVs by electroporation.RESULTSThe HEKT 293 cell line was successfully modified permanently by a lentiviral vector to express ICAM-1 on the surface of the derived EVs. The ELISA and western blot tests established the binding affinity of targeted EVs for recombinant LFA-1 with a remarkable difference from non-targeted EVs. Furthermore, flow cytometry results revealed noteworthy differences in the binding of LFA-1-positive, non-targeted EVs, and targeted EVs to LFA-1-negative cells. Finally, imaging and flow cytometry indicated that newly produced EVs could efficiently interact with T cells and functionally deliver loaded plasmids to them.CONCLUSIONThese LFA-1-targeted EVs were able to interact with T cells as their recipient cells. They can be utilized as an ideal delivery system to transfer various biomolecules to T cells, facilitating immunotherapies or other cell-based treatments.

2023-10-01·Cancer Letters

Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo

Article

作者: Ries, Alexander ; Kopatz, Verena ; Dome, Balazs ; Grusch, Michael ; Stefanelli, Alessia ; Emminger, Dominik ; Hoda, Mir A ; Hoetzenecker, Konrad ; Berger, Walter ; Reid, Glen ; Heffeter, Petra ; Eder, Sebastian ; Zitta, Benjamin ; Johnson, Thomas G ; Schelch, Karin

Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.

100 项与 Asbestos & Dust Diseases Research Institute 相关的药物交易

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100 项与 Asbestos & Dust Diseases Research Institute 相关的转化医学

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