Abstract
The administration of bone mesenchymal stem cells (BMSCs) could reverse experimental colitis, and the predominant mechanism in tissue repair seems to be related to their paracrine activity. BMSCs derived extracellular vesicles (BMSC-EVs), including mcirovesicles and exosomes, containing diverse proteins, mRNAs and micro-RNAs, mediating various biological functions, might be a main paracrine mechanism for stem cell to injured cell communication. We aimed to investigate the potential alleviating effects of BMSC-EVs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Intravenous injection of BMSC-EVs attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI) and histological colonic damage. In inflammation response, the BMSC-EVs treatment significantly reduced both the mRNA and protein levels of nuclear factor kappaBp65 (NF-κBp65), tumor necrosis factor-alpha (TNF-α), induciblenitric oxidesynthase (iNOS) and cyclooxygenase-2 (COX-2) in injured colon. Additionally, the BMSC-EVs injection resulted in a markedly decrease in interleukin-1β (IL-1β) and an increase in interleukin-10 (IL-10) expression. Therapeutic effect of BMSC-EVs associated with suppression of oxidative perturbations was manifested by a decrease in the activity of myeloperoxidase (MPO) and Malondialdehyde (MDA), as well as an increase in superoxide dismutase (SOD) and glutathione (GSH). BMSC-EVs also suppressed the apoptosis via reducing the cleavage of caspase-3, caspase-8 and caspase-9 in colitis rats. Data obtained indicated that the beneficial effects of BMSC-EVs were due to the down regulation of pro-inflammatory cytokines levels, inhibition of NF-κBp65 signal transduction pathways, modulation of anti-oxidant/ oxidant balance, and moderation of the occurrence of apoptosis.
Highlights
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), refers to a tract of chronic, idiopathic inflammatory disorders of the intestinal which are characterised by recurrent abdominal pain, protracted diarrhea, hardly cured stool with pus, blood and mucous[1]
We mainly focused on the therapeutic effect of bone mesenchymal stem cells (BMSCs)-extracellular vesicles (EVs), the major part of the paracrine mechanism of BMSCs, in experimental colitis induced by trinitrobenzene sulfonic acid (TNBS)
Our results showed that the expression of TNF-α, IL-1β, COX-2 and induciblenitric oxidesynthase (iNOS) in colonic tissues was significantly higher in TNBS-treated rats compared to the control group, while BMSC-EVs treatment efficiently reduced the overexpression of these pro-inflammatory enzymes, playing a key role in the antiinflammatory properties
Summary
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), refers to a tract of chronic, idiopathic inflammatory disorders of the intestinal which are characterised by recurrent abdominal pain, protracted diarrhea, hardly cured stool with pus, blood and mucous[1]. Patients with IBD frequently experience relapse, and current medical therapies including corticosteroids, aminosalicylates and immunosuppressants, are not always able to keep patients in remission for a long term. The first report of a clinical trial of cell therapy using autologous stem cells published in 2005 stated that stem cells were feasible and effective for the treatment of fistulas in Crohn's disease[2]. Many other experiments got the similar conclusions that stem cell was effective in the treatment of IBD[3]. Our previous study demonstrated that administration of bone marrow-derived mesenchymal stem cells could alleviate experimental colitis by modulating nuclear factor-κB-mediated pro-inflammatory response [4]. The application of BMSCs has been limited by the cancer risk
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