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

Author:

Linard Christine1,Busson Elodie2,Holler Valerie1,Strup-Perrot Carine1,Lacave-Lapalun Jean-Victor1,Lhomme Bruno1,Prat Marie2,Devauchelle Patrick3,Sabourin Jean-Christophe4,Simon Jean-Marc5,Bonneau Michel6,Lataillade Jean-Jacques2,Benderitter Marc1

Affiliation:

1. Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France

2. Research and Cell Therapy Department, Military Blood Transfusion Center, Percy Military Hospital, Clamart, France

3. Centre of Radiotherapy Scanner, National Veterinary School, Maison-Alfort, France

4. Department of Pathology, Rouen University Hospital, Rouen, France

5. Department of Radiation Oncology, Pitie-Salpetriere University Hospital, Paris, France

6. Centre of Research in Interventional Imaging, Institut National de la Recherche Agronomique, Jouy-en-Josas, France

Abstract

Abstract 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 mucosal 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-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/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.

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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