Miura Taichi, Kado Junko, Takiyama Hirotoshi, Kawano Mitsuko, Yamagiri Asako, Nishihara Shoko, Yamada Shigeru, Nakayama Fumiaki
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.
QST Hospital, National Institutes for QST, Chiba, Japan.
Adv Radiat Oncol. 2024 Jul 9;9(9):101565. doi: 10.1016/j.adro.2024.101565. eCollection 2024 Sep.
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.
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.
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.
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.
放射治疗的胃肠道副作用仍无有效治疗方法。多谱系分化应激耐受（Muse）细胞是组织干细胞，具有自发归巢至受损组织并对其进行修复的能力。多项临床试验表明，使用人骨髓来源的Muse（hBM-Muse）细胞进行干细胞治疗对多种疾病有效，但尚不清楚其对放射性肠损伤是否有效。在本研究中，我们调查了hBM-Muse细胞是否归巢至受辐射损伤的肠道并促进其修复。
在大剂量全身照射后2小时，将hBM-Muse细胞注入小鼠尾静脉。然后，进行归巢分析、隐窝分析、溴脱氧尿苷分析、末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）分析、免疫染色和生存时间测量。此外，我们分析了辐照后小鼠小肠中Muse细胞诱导因子鞘氨醇单磷酸（S1P）的表达。最后，我们研究了S1P受体2特异性拮抗剂JTE-013的给药是否抑制hBM-Muse细胞归巢至受损肠道。
辐照后小鼠肠道中S1P表达增加，hBM-Muse细胞归巢至受损肠道。辐射暴露后注射hBM-Muse细胞显著增加了隐窝数量、隐窝中的增殖细胞以及小肠组成细胞，如肠道干细胞，抑制了辐射诱导的细胞凋亡并延长了小鼠存活时间。用JTE-013治疗显著抑制了hBM-Muse细胞的肠道归巢和治疗效果。这些发现表明，hBM-Muse细胞通过S1P-S1P受体2相互作用归巢至受损肠道，对放射性肠损伤发挥治疗作用。
本研究表明，hBM-Muse细胞对放射性肠损伤有效，这表明基于hBM-Muse细胞的干细胞治疗有可能克服限制放射治疗适应症的胃肠道副作用。
