Preclinical study of Chronic radiation cystitis and cell therapy treatment

International audienceIntroduction and aim of the study: Chronic Radiocystitis Cystitis (CRC) is a disease that is sometimes a consequence of pelvic radiotherapy. It is characterized by chronic inflammation, vascular damage and tissue hypoxia leading to fibrosis. In the clinic, CRC causes pain, bleeding and incontinence. There is no curative treatment. We propose to test a cell therapy using mesenchymal stromal cells (MSC) as a new therapeutic approach. Our previous studies on radiation rectitis have shown that MSCs can modulate chronic inflammation and tissue fibrosis after irradiation.Material and methods: Our study is divided into two parts, the modeling of CRC and the effect of treatment with MSCs. Preclinical CRC modeling in rats was performed by CT-guided localized irradiation of the bladder between 20 and 80 Gray with a follow-up of 3 to 15 months after irradiation. The evolution of CRC was monitored for gene expression, histological and functional parameters.Results and statistical analysis: Measurement of urinary parameters revealed a transient hematuria increasing with time and irradiation dose without decrease in urinary volume up to 6 months. Transcriptomic analysis indicates acute inflammation at 3 months (increased expression of genes coding for CCL2, CCL5, TNFα and IL1β). It is accompanied by tissue and vascular regeneration (increased EGF and VEGF gene expression) coupled with Extra Cellular Matrix (ECM) remodeling with increased gene expression of metalloprotease MMP2, TIMP1/2/4 inhibitors, collagens Col1α2, Col3α1 and proteoglycan Cspg4.At 6 months, a second phase of inflammation (increased expression of genes coding for CCL5, IL1β, IL6 and HIF1α) is observed. It is correlated with urothelium disorganization but without tissue and vascular regeneration or remodeling of the MEC.Conclusion: These initial results are in favor of the establishment of CRC 6 months after irradiation, characterized by chronic inflammation, signs of hypoxia, hematuria and urothelium disorganization. Analysis of the kinetics over longer periods of time will characterize the evolution towards a confirmed CRC with fibrosis. The second phase of the study is underway to evaluate whether treatment with MSCs could limit fibrogenesis by inhibiting inflammatory pathways and increasing angiogenesis. Our results will provide data regarding the anti-fibrotic potential of MSCs and the treatment of CRC with MSCs