Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses.
OBJECTIVE
To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD.


METHODS
A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by measuring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined.


RESULTS
Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by down-regulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4(+)CD25(+)Foxp3(+) regulatory T cells (TGF-β, IL-10, Foxp3) with a suppressive capacity on Th1-Th17 effecter responses and promoted Th2 differentiation in vivo (P < 0.05).


CONCLUSIONS
MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD.
Department of Gastroenterology, Chinese PLA General Hospital, Medical College of PLA, Beijing 100853, China.
Qian-Qian
QQ
Chen
Li
L
Yan
Chang-Zheng
CZ
Wang
Wei-Hua
WH
Wang
Hui
H
Shi
Bin-Bin
BB
Su
Qing-Huan
QH
Zeng
Hai-Tao
HT
Du
Jun
J
Wan
D000818:Animals; D015551:Autoimmunity; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D058948:Cell Tracking; D002478:Cells, Cultured; D003092:Colitis / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D014945:Wound Healing
D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D019394:Ki-67 Antigen; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D049452:Green Fluorescent Proteins; D014302:Trinitrobenzenesulfonic Acid
Immunomodulation; Inflammatory bowel disease; Inflammatory response; Mesenchymal stem cells; Therapy; Transplantation; Trinitrobenzene sulfonic acid colitis