Abstract 1808: Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells

Abstract

Abstract Mesenchymal stem cells (MSCs) are being investigated for several therapeutic applications, including cancer, inflammation, tissue repair, and transplantation because of their ability to home to injured and inflamed tissues. Despite the large number of preclinical studies investigating engineered MSCs as therapeutic agents and numerous clinical trials investigating MSCs for other therapeutic applications, there have only been a handful of clinical trials investigating MSCs for treating solid tumors, and none have progressed beyond Phase I/II. Inefficient tumor homing ability and a lack of understanding of fundamental mechanisms may contribute to the limited translational success of MSC-based therapies. We hypothesized that nanoengineering MSCs with anticancer drugs induces oxidative stress, and MSCs counteract this stress by activating Nrf2, which increases the expression of various antioxidant proteins, including CXCR4, a key mediator of MSC tumor homing. We performed global label-free, unbiased proteomics on nanoengineered MSCs using modified in-Stage technology. Our studies indicated that MSCs nanoengineered with paclitaxel underwent significant changes in the overall proteome compared to either untreated MSCs or MSCs loaded with blank nanoparticles. Analysis of molecular function profile revealed that loading paclitaxel in MSCs significantly enhanced the expression of proteins involved in the antioxidant and catalytic activity and protein binding. The biological process profile also showed a similar increase in defense response and an increase in metabolic processes. It was further found that MSCs nanoengineered with PTX lead to significant upregulation of nrf2, the master regulator of antioxidant responses, and CXCR4, a direct target of Nrf2 and a key mediator of tumor homing. Also, an increase in CXCR4 expression was directly proportional to paclitaxel loading in cells. These studies suggest nanoengineering of MSCs impacts their biology, which likely contributes to their improved tumor homing capacity in vivo. Citation Format: Drishti Sehgal, Susheel Kumar Nethi, Carmen Merali, Salim Merali, Jayanth Panyam, Swayam Prabha. Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1808.