Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs.
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.
Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France.
Christine
C
Linard
Elodie
E
Busson
Valerie
V
Holler
Carine
C
Strup-Perrot
Jean-Victor
JV
Lacave-Lapalun
Bruno
B
Lhomme
Marie
M
Prat
Patrick
P
Devauchelle
Jean-Christophe
JC
Sabourin
Jean-Marc
JM
Simon
Michel
M
Bonneau
Jean-Jacques
JJ
Lataillade
Marc
M
Benderitter
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009092:Mucous Membrane / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011349:Proctitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D011877:Radionuclide Imaging; D012007:Rectum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013552:Swine; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D055513:Connective Tissue Growth Factor; D003094:Collagen
Cellular therapy; Irradiation; Mesenchymal stem cells; Pig model