Mesenchymal stem cells (MSCs) have been shown to migrate to various tissues. There is little information on the fate and potential therapeutic efficacy of the reinfusion of MSCs following total body irradiation (TBI). We addressed this question using human MSC (hMSCs) infused to nonobese diabetic/ severe combined immunodeficient (NOD/SCID) mice submitted to TBI. Further, we tested the impact of additional local irradiation (ALI) superimposed to TBI, as a model of accidental irradiation. NOD/SCID mice were transplanted with hMSCs. Group 1 was not irradiated before receiving hMSC infusion. Group 2 received only TBI at a dose of 3.5 Gy, group 3 received local irradiation to the abdomen at a dose of 4.5 Gy in addition to TBI, and group 4 received local irradiation to the leg at 26.5 Gy in addition to TBI. Fifteen days after irradiation, quantitative and spatial distribution of the hMSCs were studied. Histological analysis of mouse tissues confirmed the presence of radio-induced lesions in the irradiated fields. Following their infusion into nonirradiated animals, hMSCs homed at a very low level to various tissues (lung, bone marrow, and muscles) and no significant engraftment was found in other organs. TBI induced an increase of engraftment levels of hMSCs in the brain, heart, bone marrow, and muscles. Abdominal irradiation (AI) as compared with leg irradiation (LI) increased hMSC engraftment in the exposed area (the gut, liver, and spleen). Hind LI as compared with AI increased hMSC engraftment in the exposed area (skin, quadriceps, and muscles). An increase of hMSC engraftment in organs outside the fields of the ALI was also observed. Conversely, following LI, hMSC engraftment was increased in the brain as compared with AI. This study shows that engraftment of hMSCs in NOD/ SCID mice with significantly increased in response to tissue injuries following TBI with or without ALI. ALI induced an increase of the level of engraftment at sites outside the local irradiation field, thus suggesting a distant (abscopal) effect of radiation damage. This work supports the use of MSCs to repair damaged normal tissues following accidental irradiation and possibly in

The therapeutic potential of bone marrow-derived human mesenchymal stem cells (hMSC) has recently been brought into the spotlights of many fields of research. One possible application of the approach is the repair of tissue injuries related to side effects of radiotherapy. The first challenge in cell therapy is to assess the quality of the cell and the ability to retain their differentiation potential during the expansion process. Efficient delivery to the sites of intended action is also necessary. We addressed both challenges using hMSC cultured and then infused to non-obese diabetes/severe combined immunodeficiency (NOD/SCID) mice submitted to total body irradiation. Furthermore, we tested the impact of additional abdominal irradiation superimposed to total body irradiation (TBI), as a model of local therapeutic irradiation. Our results showed that the hMSC used for transplant have been expanded without significant loss in their differentiation capacities. After transplantation into adult unconditioned mice, hMSC not only migrate in bone marrow but also into other tissues. Total body irradiation increased hMSC implantation in bone marrow and muscle and further led to engraftment in brain, heart and liver. Local irradiation in addition to TBI, increased homing of injected cells to the injured tissues and to other tissues outside the local irradiation field. Morphological recovery of irradiated tissues after MSC transplantation and/or differentiation of MSC into specific organ cell types needs to be investigated. This study suggests that using the potential of hMSC to home to various organs in response to tissue injuries might be a strategy to repair the radiation-induced damages.

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It has been suggested that human mesenchymal stem cells (hMSC) could be used to repair numerous injured tissues. We have studied the potential use of hMSC to limit radiation-induced skin lesions. Immunodeficient NOD/SCID mice were locally irradiated to the leg (30 Gy, dose rate 2.7 Gy/min) using a (60)Co source to induce a severe skin lesion. Cultured bone marrow hMSC were delivered intravenously to the mice. The irradiated skin samples were studied for the presence of the human cells, the severity of the lesions and the healing process. Macroscopic analysis and histology results showed that the lesions were evolving to a less severe degree of radiation dermatitis after hMSC transplant when compared to irradiated non-transplanted controls. Clinical scores for the studied skin parameters of treated mice were significantly improved. A faster healing was observed when compared to untreated mouse. Immunohistology and polymerase chain reaction analysis provided evidence that the human cells were found in the irradiated area. These results suggest a possible use of hMSC for the treatment of the early phase of the cutaneous radiation syndrome. A successful transplant of stem cells and subsequent reduction in radiation-induced complication may open the road to completely new strategies in cutaneous radiation syndrome therapy.

Patients who undergo pelvic or abdominal radiotherapy may develop acute and/or chronic side effects resulting from gastrointestinal tract (GIT) alterations. In this study, we address the question of the regenerative capability of mesenchymal stem cells (MSC) after radiation-induced GIT injury. We also propose cellular targets of MSC therapy. We report that the infusion of human bone marrow-derived MSC (hMSC) provides a therapeutic benefit to NOD/SCID mice undergoing radiation-induced GIT failure. We observed that hMSC treatment brings about fast recovery of the small intestine (structure and function) in mice with reversible alterations and extends the life of mice with irreversible GIT disorders. The effects of hMSC are a consequence of their ability to improve the renewal capability of small intestinal epithelium. hMSC treatment favors the re-establishment of cellular homeostasis by both increasing endogenous proliferation processes (Ki67 immunostaining) and inhibiting apoptosis (TUNEL staining) of radiation-induced small intestinal epithelial cells. Our results suggest that MSC infusion may be used as a therapeutic treatment to limit radiation-induced GIT damage.

Patients who undergo pelvic radiotherapy may develop severe and chronic complications resulting from gastrointestinal alterations. The lack of curative treatment highlights the importance of novel and effective therapeutic strategies. We thus tested the therapeutic benefit of mesenchymal stem cells (MSC) treatment and proposed molecular mechanisms of action. MSC efficacy was tested in an experimental model of radiation-induced severe colonic ulceration histologically similar to that observed in patients. In this model, MSC from bone marrow were administered intravenously, immediately or three weeks (established lesions) after irradiation. MSC therapy reduces radiation-induced colonic ulceration and increases animal survival. MSC treatment induces therapeutic efficacy whatever the time of cell infusion. Infused-MSC engraft in the colon but also increase endogenous MSC mobilization in blood that have lasting benefits over time. In vitro analysis demonstrates that the MSC effect is mediated by paracrine mechanisms through the non-canonical WNT (Wingless integration site) pathway. In irradiated rat colons, MSC treatment increases the expression of the non-canonical WNT4 ligand by epithelial cells. The epithelial regenerative process is improved after MSC injection by stimulation of colonic epithelial cells positive for SOX9 (SRY-box containing gene 9) progenitor/stem cell markers. This study demonstrates that MSC treatment induces stimulation of endogenous host progenitor cells to improve the regenerative process and constitutes an initial approach to arguing in favor of the use of MSC to limit/reduce colorectal damage induced by radiation.

Non-neoplastic tissues around an abdomino-pelvic tumor can be damaged by the radiotherapy protocol, leading to chronic gastrointestinal complications that affect the quality of life with substantial mortality. Stem cell-based approaches using immunosuppressive bone marrow mesenchymal stem cells (MSCs) are promising cell therapy tools. In a rat model of radiation proctitis, we evidenced that a single MSC injection reduces colonic mucosa damages induced by ionizing radiation with improvement of the re-epithelization process for up to 21 days. Immune cell infiltrate and inflammatory molecule expressions in the colonic mucosa were investigated. We report that MSC therapy specifically reduces T-cell infiltration and proliferation, and increases apoptosis of radiation-activated T cells. We assessed the underlying molecular mechanisms and found that interleukin-10 and regulatory T lymphocytes are not involved in the immunosuppressive process in this model. However, an increased level of corticosterone secretion and HSD11b1 (11β-hydroxysteroid dehydrogenase type 1)-steroidogenic enzyme expression was detected in colonic mucosa 21 days after MSC treatment. Moreover, blocking the glucocorticoid (GC) receptor using the RU486 molecule statistically enhances the allogenic lymphocyte proliferation inhibited by MSCs in vitro and abrogates the mucosal protection induced by MSC treatment in vivo. Using the irradiation model, we found evidence for a new MSC immunosuppressive mechanism involving GCs.

Ionizing radiation is effective to treat malignant pelvic cancers, but the toxicity to surrounding healthy tissue remains a substantial limitation. Early and late side effects not only limit the escalation of the radiation dose to the tumor but may also be life-threatening in some patients. Numerous preclinical studies determined specific mechanisms induced after irradiation in different compartments of the intestine. This review outlines the complexity of the pathogenesis, highlighting the roles of the epithelial barrier in the vascular network, and the inflammatory microenvironment, which together lead to chronic fibrosis. Despite the large number of pharmacological molecules available, the studies presented in this review provide encouraging proof of concept regarding the use of mesenchymal stromal cell (MSC) therapy to treat radiation-induced intestinal damage. The therapeutic efficacy of MSCs has been demonstrated in animal models and in patients, but an enormous number of cells and multiple injections are needed due to their poor engraftment capacity. Moreover, it has been observed that although MSCs have pleiotropic effects, some intestinal compartments are less restored after a high dose of irradiation. Future research should seek to optimize the efficacy of the injected cells, particularly with regard to extending their life span in the irradiated tissue. Moreover, improving the host microenvironment, combining MSCs with other specific regenerative cells, or introducing new tissue engineering strategies could be tested as methods to treat the severe side effects of pelvic radiotherapy.