HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity

• Published in: PloS one 2015-05, Vol.10 (5), p.e0124420-e0124420
• Main Authors: Wang, Hua, Sun, Rui-Ting, Li, Yang, Yang, Yue-Feng, Xiao, Feng-Jun, Zhang, Yi-Kun, Wang, Shao-Xia, Sun, Hui-Yan, Zhang, Qun-Wei, Wu, Chu-Tse, Wang, Li-Sheng
• Format: Article
• Language: English
• Subjects: Abdomen; Adenoviruses; Animals; Apoptosis; Background radiation; Biological response modifiers; Biology; Cell growth; Cell proliferation; Complications; Complications and side effects; Cytokines; Cytokines - blood; Disease; Disease Models, Animal; Engraftment; Enzyme-linked immunosorbent assay; Epithelial cells; Female; Flow cytometry; Gamma rays; Gastrointestinal diseases; Gene expression; Gene therapy; Genes; Genetic modification; Genetic Therapy; Genetically modified organisms; Growth factors; Hematology; Hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - therapeutic use; HGF gene; Histopathology; Humans; Immunity; Immunophenotyping; Infections; Inflammation; Inflammation Mediators - metabolism; Injury prevention; Interferon; Interleukin 10; Intestine; Intestines - immunology; Intestines - injuries; Laboratory animals; Lymph nodes; Lymph Nodes - pathology; Lymphatic diseases; Lymphocytes; Medicine; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchyme; Mice, Inbred C57BL; Nuclear accidents & safety; Pathology; Peyer's Patches - pathology; Proliferating cell nuclear antigen; Radiation; Radiation (Physics); Radiation dosage; Radiation effects; Radiation injuries; Radiation Injuries - blood; Radiation Injuries - immunology; Radiation Injuries - therapy; Recovery; Repair; Rodents; Small intestine; Staining; Stem cell transplantation; Stem cells; Transduction, Genetic; Tumor necrosis factor-α; Umbilical cord; Zonula occludens-1 protein; α-Interferon; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124420

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). 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. 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. 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.