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Preclinical study of chronic radiation cystitis and cell therapy treatment
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International audience. Purpose or ObjectiveChronic radiocystitis (CRC) is a consecutive pathology of pelvic irradiation characterized by chronic inflammation occasionally progressing to fibrosis with symptoms such as pain and bleeding. Previous studies on radiation rectitis have shown that Mesenchymal Stem Cells (MSCs) can reverse chronic inflammation and fibrosis after irradiation. In a preclinical model of CRC, we further investigated whether MSC infusion may limit inflammation and fibrosis. Materials and MethodsOur study is divided into two parts, the design of a rat model of CRC then the influence of MSC infusion on CRC. CRC was induced by localized irradiation of the whole bladder with two beams, guided by tomography using the Small Radiation Research Platform (SARRP). A dose range of 20 to 80 Gy with a follow-up of 3 to 12 months post-irradiation was performed. Then we retained to use an irradiation of 40 Gy, followed 4 months later by an intravenous injection of 5 million of MSCs, administered every two weeks (3 injections in total). Physiological, histological and molecular monitoring was performed over 12 months after irradiation (figure 1).Figure 1: Experimental designResultsResults showed the onset of CRC as early as 6 months after irradiation, with chronic inflammation, hematuria, urothelium disorganization and fibrosis increasing with time (figure 2).We observed that the intensity and frequency of hematuria were proportional to the radiation dose with a threshold at 40 Gy and the onset of bleeding from 60 days post-irradiation.Inflammation with overexpression of CCL5 (5-fold; p-value<0.05), IL1β (7-fold; p-value<0.001) and IL6 (7.5-fold; p-value<0.01) genes was observed 6 months after irradiation at 40 Gy. Longer periods of time are under investigation.Fibrosis initiated at 6 months after irradiation and increased with time and irradiation dose.Urothelium lesions (based on urothelium-free areas with a decrease in uroplakine III) were also visible at 6 months after irradiation. At 10 months after irradiation a regeneration of the urothelium was noticeable with overexpression of cytokeratin 5 (marker of basal stem cells). However, this regeneration seems defective since at 12 months after irradiation, a hyperplasia was confirmed in irradiated rats (p<0.01 value).Treatment with MSCs delayed the onset of bleeding up to 300 days after irradiation. This correlated with the vascular lesions observed in cystoscopy, which showed that the injection of MSCs in irradiated rats reduced vascular lesions up to 12 months post-irradiation. Furthermore, the infusion of MSCs decreased hyperplasia in comparison of irradiated control (figure 2). Figure 2: Main results: White arrow = beginning of hematuria. Black arrows = Vascular lesionConclusionTreatment with MSCs resulted in delayed hematuria as well as a decrease in vascular damage and hyperplasia. Analysis of the effect of MSCs on inflammation, urothelium regeneration and fibrosis is ongoing.
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