**6. Conclusions**

RT is an indispensable part of clinical cancer treatment, and more than 50% of cancer patients received RT [161]. Though the radiation doses and related radiotoxicity have been remarkably reduced due to modern RT techniques, radiation injury in normal tissue is still a thorny problem affecting patients' life quality and even survival rate. MSCs have abundant resources, excellent regenerative potential, immunomodulatory features, showing therapeutic potential in mitigating radiation injury in preclinical studies. Moreover, chemical, physical, or pharmaceutical preconditioning greatly enhanced the therapeutic potency of MSCs [162]. The overexpression of desired factors (antioxidation, differentiation, immunomodulation, angiogenesis, anti-apoptotic, and regeneration) targeting the specific disease model represents a novel approach in precision medicine. Because the local harsh environment and death signals cause MSCs to be rarely retained in the transplanted sites, MSCs-secretome or a combination with tissue engineering are emerging as a new trend. Notably, radiation-induced skin and intestine injury are easy to be aware of. Radiotoxicity that developed months or years after RT is challenging to be diagnosed or predicted early. In order to reduce or prevent radiotoxicity, more advanced radiotherapy technologies, such as IMRT and IGRT, need to be created. On the other hand, the application of MSCs as regenerative/repair agents when symptoms are presented or as preventive medicine directly after RT also needs careful consideration. The combination of prevention and regeneration/repair is the key to protect radiotherapy patients. Though there are many obstacles in the clinical application of MSCs, there is already a clinical trial evaluating the efficacy of MSC injections for the treatment of chronic radiotherapy-induced complications (PRISME, NCT02814864). We expect a promising future of MSCs therapy in mitigating radiation injury.

**Author Contributions:** K.-X.W., wrote the manuscript; T.-S.L., and L.L., revised and proved the final manuscript; W.-W.C., X.Y., A.-B.T., and T.L., made suggestions and revisions in the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported by the National Natural Science Foundation of China (grant no. 81802086, 81802063, 81971817), the Natural Science Foundation of Jiangsu Province (grant no. BK20180995), the Specialized Research Fund for Senior Personnel Program (grant no. D2019028, no. D2017022), and the Young Science and Technology Innovation Team (grant no. TD202005) of Xuzhou Medical University, and a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology, Japan.

**Conflicts of Interest:** The authors confirm that this article content has no conflict of interest.

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