Stem cell therapy using bone marrow-derived Muse cells repairs radiation-induced intestinal injury through their intestine-homing via S1P-S1PR2 interaction

Abstract

PurposeThere is still no effective treatment for the gastrointestinal side effects of radiation therapy. Multilineage-differentiating stress enduring (Muse) cells are tissue stem cells that have the ability to spontaneously homing in on injured tissues and repairing them. Several clinical trials have shown that stem cell therapy using human bone marrow-derived Muse (hBM-Muse) cells is effective in treating various diseases, but it is not known whether they are effective in treating radiation-induced intestinal injury. In this study, we investigated whether hBM-Muse cells homing to the radiation-damaged intestine and promote its repair. Methods and MaterialshBM-Muse cells were injected into the tail vein of mice 2 hours after high-dose total body irradiation. Then, homing analysis, crypt assay, BrdU assay, TUNEL assay, immunostaining, and survival time measurements were performed. In addition, we analyzed the expression of sphingosine monophosphate (S1P), a Muse cell inducing factor, in the mouse small intestine after irradiation. Finally, we investigated whether administration of JTE-013, an S1P receptor 2 (S1PR2)-specific antagonist, inhibits hBM-Muse cells homing to the injured intestine. ResultsS1P expression increased in mouse intestine after irradiation, with hBM-Muse cells homing in on the injured intestine. Injection of hBM-Muse cells after radiation exposure significantly increased the number of crypts, proliferating cells in the crypts, and small intestinal component cells such as intestinal stem cells, inhibited radiation-induced apoptosis, and prolonged mouse survival. Treatment with JTE-013 significantly inhibited intestinal homing and therapeutic effects of hBM-Muse cells. These findings indicate that hBM-Muse cells homed in on the injured intestine through the S1P-S1PR2 interaction to exert therapeutic effects on the radiation-induced intestinal injury. ConclusionThis study indicates that hBM-Muse cells are effective in treating radiation-induced intestinal injury, suggesting that hBM-Muse cell-based stem cell therapy has the potential to overcome the gastrointestinal side effects that limit the indications for radiation therapy.