Genetic modification to induce CXCR2 overexpression in mesenchymal stem cells enhances treatment benefits in radiation-induced oral mucositis

Abstract

Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR2-overexpressing MSCs (MSCsCXCR2) for mucositis treatment. Indeed, MSCsCXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSCCXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.

Mesenchymal stem cells overexpressing heme oxygenase‐1 ameliorate lipopolysaccharide‐induced acute lung injury in rats

“…Certainly, the cellular migration activity influences the number of homing MSCs. Moreover, the migration activity is strongly associated with chemokines and their receptors such as chemokine C‐X‐C motif chemokine 12 and CXCR2 (Chang et al, ; Shen et al, ). Whether HO‐1 overexpression influences the migration activity of MSCs by modulating the expression and/or function of chemokines and their receptor remains to be investigated in future studies.…”

Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy

“…Similarly, CCL2 expression by cancer-associated fibroblasts has been shown to support the growth of breast cancer stem cells (92), while CXCR4 was shown to be enriched in a subset of glioma cancer stem cells (93). Furthermore, CXCR2 is expressed in MSC and CXCR2 overexpressing MSCs can be used to accelerate mucosa wound healing (94). Both CXCR5 and CXCR4 are involved in metastasis of PCSLC prostate cancer stem-like cells (95), and inhibition of CXCR4 alters the homing of quiescent stem-like prostate cancer cells to bone (96).…”

Photobiomodulation at Multiple Wavelengths Differentially Modulates Oxidative Stress In Vitro and In Vivo

“…While the etiology and the pathogenic mechanisms of OM have not been fully elucidated yet, several studies have reported a major role of DNA damage and reactive oxygen species (ROS) during the early phases of oral and intestinal mucositis [ 4 – 7 ]. Thus, either limiting ROS generation or increasing their detoxification during CT/RT stands as a rational and promising strategy to prevent OM onset and/or reduce its severity [ 8 – 11 ].…”