Stem Cell Therapy Using Bone Marrow-Derived Muse Cells Repairs Radiation-Induced Intestinal Injury Through Their Intestine-Homing via Sphingosine Monophosphate-Sphingosine Monophosphate Receptor 2 Interaction

Taichi Miura; Junko Kado; Hirotoshi Takiyama; Mitsuko Kawano; Asako Yamagiri; Shoko Nishihara; Shigeru Yamada; Fumiaki Nakayama

doi:10.1016/j.adro.2024.101565

Stem Cell Therapy Using Bone Marrow-Derived Muse Cells Repairs Radiation-Induced Intestinal Injury Through Their Intestine-Homing via Sphingosine Monophosphate-Sphingosine Monophosphate Receptor 2 Interaction

Adv Radiat Oncol. 2024 Jul 9;9(9):101565. doi: 10.1016/j.adro.2024.101565. eCollection 2024 Sep.

Authors

Taichi Miura¹, Junko Kado¹, Hirotoshi Takiyama², Mitsuko Kawano¹, Asako Yamagiri¹, Shoko Nishihara^{3

4}, Shigeru Yamada², Fumiaki Nakayama^{1

5}

Affiliations

¹ Regenerative Therapy Research Group, Department of Radiation Regulatory Science Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum Science and Technology (QST), Chiba, Japan.
² QST Hospital, National Institutes for QST, Chiba, Japan.
³ Glycan and Life Systems Integration Center (GaLSIC), Soka University, Hachioji, Tokyo, Japan.
⁴ Laboratory of Cell Biology, Department of Biosciences, Graduate School of Science and Engineering, Soka University, Hachioji, Tokyo, Japan.
⁵ Donation Course of Advanced Regenerative Plastic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Abstract

Purpose: There 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 home in on injured tissues and repair 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 are homing to the radiation-damaged intestine and promote its repair.

Methods and materials: hBM-Muse cells were injected into the tail vein of mice 2 hours after high-dose total body irradiation. Then, homing analysis, crypt assay, bromodeoxyuridine assay, Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (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 the administration of JTE-013, an S1P receptor 2-specific antagonist, inhibits hBM-Muse cells homing to the injured intestine.

Results: S1P 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-S1P receptor 2 interaction to exert therapeutic effects on the radiation-induced intestinal injury.

Conclusions: This 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 gastrointestinal side effects that limit the indications for radiation therapy.