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Abstract The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE(−/−) mice to a single dose of 0, 0.05, 0.5 or 1 Gy of 137Cs (γ) administered at a 10.35 mGy min−1 dose rate and evaluated short-term (1–10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6CHigh and Ly6Low cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6CLow monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation.

Anastomotic leak occurrence is a severe complication after colorectal surgery. Considering the difficulty of treating these leaks and their impact on patient care, there is a strong need for an efficient prevention strategy. We evaluated a combination of extracellular vesicles (EVs) from rat adipose-derived stromal cells with a thermoresponsive gel, Pluronic® F127 (PF-127) to prevent anastomotic leaks. The pro-regenerative and immunomodulatory potencies of EVs are assessed in vitro. In vivo efficacy are assessed in rat with a colonic anastomosis model after irradiation. Endoscopic, anatomical and histological data show a consistent effect of EVs + gel on the healing of colonic anastomosis. These results are illustrated by a smaller anastomotic ulcer size, less fibrosis and less inflammatory infiltrations in the EVs + gel group. This multi-modal investigation is the first to point-out the translational potential of EVs combined with PF-127 for the healing of high-risk colorectal anastomosis., Competing Interests: Competing interests: H.A., N.M., G.P., A.C.S., C.D., A.C., A.B., B.M., A.M., O.C., I.A.F. declare no competing interest. G.R. received personal fees from FUJIFILM, MEDTRONIC, and grants from NORGINE. F.G., A.S., C.W., and G.R. are co-founders of the spin-off Evora Biosciences. A.S. and C.W. are co-founders of the spin-off EverZom., (© 2024. The Author(s).)

Background: Cellular therapy seems to be an innovative therapeutic alternative for which mesenchymal stem cells (MSCs) have been shown to be effective for interstitial and hemorrhagic cystitis. However, the action of MSCs on chronic radiation cystitis (CRC) remains to be demonstrated. The aim of this study was to set up a rat model of CRC and to evaluate the efficacy of MSCs and their mode of action., Methods: CRC was induced by single-dose localized irradiation of the whole bladder using two beams guided by tomography in female Sprague-Dawley rat. A dose range of 20-80 Gy with follow-up 3-12 months after irradiation was used to characterize the dose effect and the kinetics of radiation cystitis in rats. For the treatment, the dose of 40 Gy was retained, and in order to potentiate the effect of the MSCs, MSCs were isolated from adipose tissue. After expansion, they were injected intravenously during the pre-chronic phase. Three injections of 5 million MSCs were administered every fortnight. Follow-up was performed for 12 months after irradiation., Results: We observed that the intensity and frequency of hematuria are proportional to the irradiation dose, with a threshold at 40 Gy and the appearance of bleeding from 100 days post-irradiation. The MSCs reduced vascular damage as well as damage to the bladder epithelium., Conclusions: These results are in favor of MSCs acting to limit progression of the chronic phase of radiation cystitis. MSC treatment may afford real hope for all patients suffering from chronic radiation cystitis resistant to conventional treatments., (© 2023. The Author(s).)

Embedding mesenchymal stromal cells (MSCs) in biomaterial is a subject of increasing interest in the field of Regenerative Medicine. Speeding up the clinical use of MSCs is dependent on the use of non-syngeneic models in accordance with Good Manufacturing Practices (GMP) requirements and on costs. To this end, in this study, we analyzed the in vivo host immune response following local injection of silanized hydroxypropyl methylcellulose (Si-HPMC)-embedded human MSCs in a rat model developing colorectal damage induced by ionizing radiation. Plasma and lymphocytes from mesenteric lymph nodes were harvested in addition to colonic tissue. We set up tests, using flow cytometry and a live imaging system, to highlight the response to specific antibodies and measure the cytotoxicity of lymphocytes against injected MSCs. We demonstrated that Si-HPMC protects MSCs from specific antibodies production and from apoptosis by lymphocytes. We also observed that Si-HPMC does not modify innate immune response infiltrate in vivo , and that in vitro co-culture of Si-HPMC-embedded MSCs impacts macrophage inflammatory response depending on the microenvironment but, more importantly, increases the macrophage regenerative response through Wnt -family and VEGF gene expression. This study furthers our understanding of the mechanisms involved, with a view to improving the therapeutic benefits of biomaterial-assisted cell therapy by modulating the host immune response. The decrease in specific immune response against injected MSCs protected by Si-HPMC also opens up new possibilities for allogeneic clinical use., (© The Author(s) 2022. Published by Oxford University Press.)