• Christelle Durand, Sophie Pezet, Hélène Eutamène, Christelle Demarquay, Noëlle Mathieu, Lara Moussa, Rachel Daudin, Valérie Holler, Jean-Christophe Sabourin, Fabien Milliat, Agnès François, Vassilia Theodorou, Radia Tamarat, Marc Benderitter, and Alexandra Sémont.
• aInstitut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LR2I, Fontenay-aux-Roses, France bBrain Plasticity Unit, ESPCI-ParisTech, Paris, France cCentre National de la Recherche Scientifique, UMR 8249, Paris, France dParis Science et Lettres, Paris, France eINRA, EI-Purpan, UMR 1331 TOXALIM, Neuro-Gastroenterology and Nutrition Team, Toulouse, France fDepartment of Pathology, Rouen University Hospital, Rouen, France gInstitut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, L3R, Fontenay-aux-Roses, France.
• Pain. 2015 Aug 1; 156 (8): 1465-76.

AbstractEach year, millions of people worldwide are treated for primary or recurrent pelvic malignancies, involving radiotherapy in almost 50% of cases. Delayed development of visceral complications after radiotherapy is recognized in cancer survivors. Therapeutic doses of radiation may lead to the damage of healthy tissue around the tumor and abdominal pain. Because of the lack of experimental models, the underlying mechanisms of radiation-induced long-lasting visceral pain are still unknown. This makes managing radiation-induced pain difficult, and the therapeutic strategies proposed are mostly inefficient. The aim of our study was to develop an animal model of radiation-induced visceral hypersensitivity to (1) analyze some cellular and molecular mechanisms involved and (2) to test a therapeutic strategy using mesenchymal stromal cells (MSCs). Using a single 27-Grays colorectal irradiation in rats, we showed that such exposure induces a persistent visceral allodynia that is associated with an increased spinal sensitization (enhanced p-ERK neurons), colonic neuroplasticity (as increased density of substance P nerve fibers), and colonic mast cell hyperplasia and hypertrophy. Mast cell stabilization by ketotifen provided evidence of their functional involvement in radiation-induced allodynia. Finally, intravenous injection of 1.5 million MSCs, 4 weeks after irradiation, induced a time-dependent reversion of the visceral allodynia and a reduction of the number of anatomical interactions between mast cells and PGP9.5+ nerve fibers. Moreover, unlike ketotifen, MSC treatment has the key advantage to limit radiation-induced colonic ulceration. This work provides new insights into the potential use of MSCs as cellular therapy in the treatment of pelvic radiation disease.

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