HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity.
BACKGROUND
Effective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs), which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF)-gene-modified MSCs on radiation-induced intestinal injury (RIII).


METHODS
Female 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis.


RESULTS
The histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer's patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ), increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells.


CONCLUSIONS
Treatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII.
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Hua
H
Wang
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China; College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100022, PR China.
Rui-Ting
RT
Sun
Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Yang
Y
Li
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Yue-Feng
YF
Yang
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Feng-Jun
FJ
Xiao
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Yi-Kun
YK
Zhang
Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Shao-Xia
SX
Wang
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Hui-Yan
HY
Sun
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Qun-Wei
QW
Zhang
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China; Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University，Chengdu, 610041, PR China.
Chu-Tse
CT
Wu
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Li-Sheng
LS
Wang
D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007109:Immunity; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000293:injuries*; D008198:Lymph Nodes / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008810:Mice, Inbred C57BL; D010581:Peyer's Patches / Q000473:pathology; D011832:Radiation Injuries / Q000097:blood / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic
D016207:Cytokines; D018836:Inflammation Mediators; D017228:Hepatocyte Growth Factor