In vitro impact of the radiation-induced bystander effect mediated by mesenchymal stem cells on leukemic cell migration: implications for the CXCL12/CXCR4 axis.

Abstract

Purpose: The hematopoietic microenvironment, particularly mesenchymal stem cells (MSCs), plays a crucial role in hematopoiesis and cell migration. MSCs influence hematopoietic cells through their secretome, impacting cell trafficking and homing. Leukemia disrupts this environment, and while radiotherapy targets malignant cells, it may also affect surrounding cells via the radiation-induced bystander effect (RIBE). This study investigated both the direct effects of radiation on MSCs and their bystander influence on leukemic cell migration.

Materials and methods: Mouse MSCs (C3H10T1/2) and leukemic cells (C1498) were cultured to assess radiation-induced apoptosis, DNA damage, and bystander effects. Conditioned media from irradiated MSCs were applied to C1498 cells to evaluate apoptosis, gene expression, adhesion, and migration using flow cytometry and RT-PCR.

Results: MSCs were radiation-resistant up to 4 Gy but sustained damage at 6 Gy. Irradiated MSCs secreted elevated levels of IL-1β, sICAM-1, and CXCL-12. While the bystander effect on leukemic cells was modulated by irradiated MSCs, it did not affect survival or genes related to cell migration. However, an increase in leukemic cell migration rate mediated by the CXCL-12/CXCR4 axis was noted. Inhibition of CXCR4 with AMD3100 reduced this migration, highlighting the potential of targeting this axis for therapeutic strategies.

Conclusion: The MSC-mediated bystander effect, primarily involving the CXCL-12/CXCR4 axis, appears to promote increased leukemic cell migration in vitro. While these findings provide preliminary insights into how radiotherapy may influence the hematopoietic microenvironment, further in vivo studies and validation across additional cell lines are necessary to confirm these effects and explore their potential therapeutic implications.