Umbilical cord mesenchymal stem cells modulate dextran sulfate sodium induced acute colitis in immunodeficient mice

Abstract

IntroductionInflammatory bowel diseases (IBD) are complex multi-factorial diseases with increasing incidence worldwide but their treatment is far from satisfactory. Unconventional strategies have consequently been investigated, proposing the use of cells as an effective alternative approach to IBD. In the present study we examined the protective potential of exogenously administered human umbilical cord derived mesenchymal stem cells (UCMSCs) against Dextran Sulfate Sodium (DSS) induced acute colitis in immunodeficient NOD.CB17-Prkdcscid/J mice with particular attention to endoplasmic reticulum (ER) stress.MethodsUCMSCs were injected in NOD.CB17-Prkdcscid/J via the tail vein at day 1 and 4 after DSS administration. To verify attenuation of DSS induced damage by UCMSCs, Disease Activity Index (DAI) and body weight changes was monitored daily. Moreover, colon length, histological changes, myeloperoxidase and catalase activities, metalloproteinase (MMP) 2 and 9 expression and endoplasmic reticulum (ER) stress related proteins were evaluated on day 7.ResultsUCMSCs administration to immunodeficient NOD.CB17-Prkdcscid/J mice after DSS damage significantly reduced DAI (1.45 ± 0.16 vs 2.08 ± 0.18, p < 0.05), attenuating the presence of bloody stools, weight loss, colon shortening (8.95 ± 0.33 cm vs 6.8 ± 0.20 cm, p < 0.01) and histological score (1.97 ± 0.13 vs 3.27 ± 0.13, p < 0.001). Decrease in neutrophil infiltration was evident from lower MPO levels (78.2 ± 9.7 vs 168.9 ± 18.2 U/g, p < 0.01). DSS treatment enhanced MMP2 and MMP9 activities (>3-fold), which were significantly reduced in mice receiving UCMSCs. Moreover, positive modulation in ER stress related proteins was observed after UCMSCs administration.ConclusionsOur results demonstrated that UCMSCs are able to prevent DSS-induced colitis in immunodeficient mice. Using these mice we demonstrated that our UCMSCs have a direct preventive effect other than the T-cell immunomodulatory properties which are already known. Moreover we demonstrated a key function of MMPs and ER stress in the establishment of colitis suggesting them to be potential therapeutic targets in IBD treatment.

Mesenchymal Stem Cells (MSC) Derived from Induced Pluripotent Stem Cells (iPSC) Equivalent to Adipose-Derived MSC in Promoting Intestinal Healing and Microbiome Normalization in Mouse Inflammatory Bowel Disease Model

“…Histologically, colonic tissues from DSS‐treated mice exhibited severe infiltration of inflammatory cells, variable degrees of colonic gland ectasia and necrosis, extensive mucosal erosion to ulceration, and occasional complete loss and collapse of mucosal architecture (Fig. B) consistent with previous studies . In contrast, colonic tissues from mice treated with either iMSC or adMSC exhibited an overall reduction in transmural inflammation, with significantly less infiltration of inflammatory cells in the lamina propria, diminished mucosal ulceration, and decreased mucosal collapse and granulation tissue formation.…”

Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis

“…MSC are capable of reducing the cells comprising a network of immune system such as dendritic cells, NK cells and T-cells [ 11 – 13 ], and also of elevating secretion of anti-inflammatory cytokines such as interleukin 10 (IL-10) and prostaglandin E2 (PGE2) [ 14 ]. These findings suggest that IBD is a disease that could be effectively treated using MSC therapy [ 15 , 16 ]. The beneficial therapeutic effects of MSC such as BM-MSC and A-MSC on a DSS-induced murine IBD model, or more specifically, a colitis model, have been reported [ 16 , 17 ].…”

Protective effect of mesenchymal stem cells on the pressure ulcer formation by the regulation of oxidative and endoplasmic reticulum stress

“…In addition, ROS is one of the key stimuli that can cause ER stress, and ER stress often accompanies an increase in ROS production 48 . Several studies have shown that MSCs can improve ER stress in animal models 22 , 49 , 50 . In animal models including renal injury induced by renal artery stenosis, spinal cord injury, and acute colitis induced by dextran sulfate sodium (DSS), the injection of MSCs significantly improved the injury or the disease activity and reduced ER stress and apoptosis 22 , 49 , 50 .…”