Repeated Autologous Bone Marrow-Derived Mesenchymal Stem Cell Injections Improve Radiation-Induced Proctitis in Pigs

Christine Linard (1) , Elodie Busson (2) , Valérie Holler (1) , Carine Strup-Perrot (1) , Jean-Victor Lacave-Lapalun (1) , Bruno Lhomme (1) , Marie Prat (2) , Patrick Devauchelle (3) , Jean-Christophe Sabourin (4) , Jean-Marc Simon (5) , Michel M. Bonneau (6) , Jean-Jacques Lataillade (2) , Marc Benderitter (1)

1 IRSN - Institut de Radioprotection et de Sûreté Nucléaire
2 Hôpital d'instruction des Armées Percy
3 ENVA - École nationale vétérinaire d'Alfort
4 CHU Rouen
5 CHU Pitié-Salpêtrière [AP-HP]
6 UE 1298 Unité Commune d'Expérimentation Animale

The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosa! damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-p/connective tissue growth factor, and by modifying the matrix meta lloproteinase/ TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.

Mots clés: Mesenchymal stem cells; Irradiation; Pig model; Cellular therapy; CONFORMAL RADIOTHERAPY; EXPERIMENTAL COLITIS; PROSTATE-CANCER; CROHNS-DISEASE; INJURY; MYOFIBROBLASTS; MACROPHAGES

Mots clés: STROMAL CELLS; REPAIR; INFLAMMATION

Domaines: Sciences du Vivant [q-bio]; Informatique [cs]

Christine Linard, Elodie Busson, Valérie Holler, Carine Strup-Perrot, Jean-Victor Lacave-Lapalun, et al.. Repeated Autologous Bone Marrow-Derived Mesenchymal Stem Cell Injections Improve Radiation-Induced Proctitis in Pigs. Stem Cells Translational Medicine, 2013, 2 (11), pp.916 - 927. ⟨10.5966/sctm.2013-0030⟩. ⟨hal-02647101⟩