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Canadian Journal of Cardiology

IMMUNOENGINEERING APPLICATION OF MXENE FOR PREVENTION OF TRANSPLANT VASCULOPATHY

      Background

      Cardiac allograft vasculopathy is an aggressive form of atherosclerosis and a major cause of mortality among patients with heart transplants. Blood vessel endothelial cells stimulate alloreactive T-lymphocytes to result in sustained inflammation. MXenes are an emerging class of nanomaterials that have significantly outperformed several existing biomaterials as anti-cancer agents, biosensors, and in anti-microbial therapies. Herein, we report the first application of titanium carbide (Ti3C2Tx) MXene nanosheets for prevention of allograft vasculopathy.

      Methods and Results

      To infer mechanisms and to ensure reproducibility of results, detailed physicochemical characterization of Ti3C2Tx MXene nanosheets was performed using scanning/transmission electron microscopy, x-ray diffraction, and x-ray photoelectron spectroscopy. In vitro studies were carried out using co-cultures of human umbilical vein endothelial cells (HUVECs) with allogeneic peripheral blood mononuclear cells, and immunomodulatory function was assessed using flow cytometry and RNA sequencing. A rat aortic transplantation model was used for in vivo validation of safety and immunomodulatory function. Ti3C2Tx MXene nanosheets were 2 to 5 μm in size and enriched with biologically active surface groups, including carboxyl, hydroxyl, and fluorine. In vitro, MXene nanosheets interacted with HUVECs and downregulated the expression of genes involved in alloantigen presentation through the class I major histocompatibility complex (IRF1, TAP1, B2M), and reduced the activation and pro-inflammatory polarization of co-cultured allogeneic lymphocytes. Consequently, RNA-Seq analysis of these lymphocytes showed that treatment with MXene nanosheets downregulated genes responsible for transplant-induced T-cell activation, cell-mediated rejection, and development of allograft vasculopathy. Furthermore, gene set enrichment analysis revealed significant negative enrichment of genes involved in interferon alpha/beta and interferon gamma signaling. Finally, in an in vivo rat model of allograft vasculopathy, treatment with Ti3C2Tx MXene nanosheets reduced lymphocyte infiltration and preserved medial smooth muscle cell integrity within transplanted aortic allografts.

      Conclusion

      These findings support the potential of Ti3C2Tx MXene nanosheets for prevention and treatment of allograft vasculopathy and other inflammatory diseases. This research also opens the door to development of Ti3C2Tx MXene technologies for other immune-sensitive regenerative medicine applications.