Cellular therapy treatment of chronic radiation cystitis in rats

Abstract

Background & Aim Chronic radiocystitis (CRC) is a pathology resulting from irradiation of the pelvic area without long term effective treatment. CRC is characterized by chronic inflammation progressing to fibrosis, fistulas and cystectomy in the most severe cases. Our laboratory have previously demonstrated that MSC treatment reverse similar damages in irradiated colon. Furthermore in a clinical phase 1/2 treatments using MSCs for hemorrhagic cystitis, which is pathology similar to CRC, was sucessfull (Ringden O et al., 2007). Based on these previous results, our objective is to evaluate whether adipose derived mesenchymal stem cells (MSCs) could be an innovative treatment of CRC. Methods, Results & Conclusion Preclinical modeling of CRC in rats (Sprague Dawley) was established by irradiating the entire bladder with a single dose of 40 Gray using the Small Animal Radiation Research Platform (SARRP, figure 1)). At four months after irradiation, animals received a treatment consisting in tree intravenous injections of 5 million of MSCs every two weeks. After irradiation and treatment, a physiological, histological and molecular follow-up was performed on 14 months (figure 2). Results have shown, without MSC treatment, an initiation of CRC at 6 months, with chronic inflammation, hypoxia, hematuria, disorganization of the urothelium and fibrosis. Analysis of urinary parameters has revealed hematuria increasing with time. Transcriptomic analysis indicates chronic inflammation (IL1β, CCL2, IL6) and hypoxia (HIF1α). Histological observations reveal a disorganization of the urothelium with loss of superficial cells and fibrosis (figure 3). Study is in progress to evaluate whether MSC treatment could limite fibrogenesis by inhibiting the inflammatory pathways and increasing angiogenesis, in our model CRC preclinical model. Our results will provide data regarding the anti-fibrotic potential of MSCs and could support their use in the treatment of CRC. Ringden O, Uzunel M, Sundberg B, et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007: 21: 2271–2276.