Reversal of Radiation Damage to Marrow Stem Cells By Mesenchymal Stem Cell Derived Vesicles

Extracellular vesicles (exosomes and microvesicles) have been found to deliver both mRNA and transcriptional modulators to target cells and affect their phenotype. Marrow mesenchymal stem cell derived vesicles (MSC-DV) have also been shown to reverse renal and hepatic injury. We have studied the capacity of MSC-DV to reverse radiation injury to marrow stem cells.

B6.SJL mice were exposed to 100 centigrade whole body radiation (WBI), and 4, 24, and 168 hours later marrow is harvested and established in culture for 24-48 hours with either human or murine marrow-derived mesenchymal stem cells (MSV-DV) or vehicle. These cells were then transplanted into 950 cGy exposed C57/BL mice and engraftment evaluated at 3 weeks to 8 months. Alternatively cells were engrafted without competition into 200 centigrade exposed mice. Significant (p<0.05) restoration of engraftment was seen in each setting; restoration of secondary engraftment was also seen. Mice were also subjected to 500 cGy WBI and injected at 6, 24 and 72 hours with human MSC-DV and peripheral blood counts determined. Granulocyte levels were restored to 86% of control at 3 weeks post irradiation and significant restoration seen at multiple other time points. Restoration was seen was seen in both peripheral blood and marrow. Further studies on the murine hematopoietic cell line, FDC-P1 exposed to 500 centigrade showed dramatic recovery on exposure to murine or human MSC-DV. Additional work, employing differential ultracentrifugation as a separative technique for vesicles, showed that a preparation with both exosomes and microvesicles was superior to either microvesicles or exosomes alone. Studies with irradiated FDC-P1 cells indicated that exposure to vesicles decreased apoptosis. These studies indicate that vesicles from marrow-derived mesenchymal stem cells from different sources have the capacity to reverse radiation damage to bone marrow stem cells. Thus administration of MSC-DV to patients exposed to radiation could represent an important new strategy in radiation mitigation.