title: Persistent visceral allodynia in rats exposed to colorectal irradiation is reversed by mesenchymal stromal cell treatment.
abstract: Each 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.
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LR2I, Fontenay-aux-Roses, France Brain Plasticity Unit, ESPCI-ParisTech, Paris, France Centre National de la Recherche Scientifique, UMR 8249, Paris, France Paris Science et Lettres, Paris, France INRA, EI-Purpan, UMR 1331 TOXALIM, Neuro-Gastroenterology and Nutrition Team, Toulouse, France Department of Pathology, Rouen University Hospital, Rouen, France Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, L3R, Fontenay-aux-Roses, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Durand
authors.forename: Sophie
authors.initials: S
authors.lastname: Pezet
authors.forename: Hélène
authors.initials: H
authors.lastname: Eutamène
authors.forename: Christelle
authors.initials: C
authors.lastname: Demarquay
authors.forename: Noëlle
authors.initials: N
authors.lastname: Mathieu
authors.forename: Lara
authors.initials: L
authors.lastname: Moussa
authors.forename: Rachel
authors.initials: R
authors.lastname: Daudin
authors.forename: Valérie
authors.initials: V
authors.lastname: Holler
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
authors.forename: Agnès
authors.initials: A
authors.lastname: François
authors.forename: Vassilia
authors.initials: V
authors.lastname: Theodorou
authors.forename: Radia
authors.initials: R
authors.lastname: Tamarat
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sémont
mesh_terms: D015746:Abdominal Pain / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D003106:Colon / Q000473:pathology / Q000528:radiation effects*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000378:metabolism / Q000628:therapy*; D006965:Hyperplasia / Q000473:pathology; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009473:Neuronal Plasticity; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000150:complications*; D051381:Rats; D016896:Treatment Outcome
chemical_list: D017027:Protein Tyrosine Phosphatases