Umbilical cord mesenchymal stem cells modulate dextran sulfate sodium induced acute colitis in immunodeficient mice
Umbilical cord mesenchymal stem cells modulate dextran sulfate sodium induced acute colitis in immunodeficient mice
复制标题
DOI：
10.1186/s13287-015-0073-6
复制
发表时间：
2015-04-16
影响因子：
7.5
通讯作者：
Russo, Francesco Paolo
中科院分区：
文献类型：
--
作者：
Banerjee, Antara;Bizzaro, Debora;Russo, Francesco Paolo
简介：炎症性肠病（IBD）是一种复杂的多因素疾病，在世界范围内发病率不断上升，但其治疗却远不令人满意。因此，人们对非常规策略进行了研究，提出使用细胞作为 IBD 的有效替代方法。在本研究中，我们检查了外源性人脐带间充质干细胞（UCMSC）对免疫缺陷型 NOD.CB17-Prkdc(scid)/J 小鼠中右旋糖酐硫酸钠（DSS）诱导的急性结肠炎的保护潜力，特别关注内质网（ER）应激。方法：通过尾静脉将 UCMSC 注射到 NOD.CB17-Prkdc(scid)/J 中。 DSS 给药后第 1 天和第 4 天。为了验证 UCMSC 对 DSS 诱导损伤的减弱作用，每天监测疾病活动指数 (DAI) 和体重变化。此外，在第 7 天评估了结肠长度、组织学变化、髓过氧化物酶和过氧化氢酶活性、金属蛋白酶 (MMP) 2 和 9 表达以及内质网 (ER) 应激相关蛋白。 结果：在 DSS 损伤后，对免疫缺陷 NOD.CB17-Prkdc(scid)/J 小鼠施用 UCMSC 显着降低了 DAI（1.45 +/- 0.16 vs 2.08 +/- 0.18，p < 0.05），减少血便、体重减轻、结肠缩短（8.95 +/- 0.33 cm vs 6.8 +/- 0.20 cm，p < 0.01）和组织学评分（1.97 +/- 0.13 vs 3.27 +/- 0.13，p < 0.001）。 MPO 水平较低，中性粒细胞浸润明显减少（78.2 +/- 9.7 vs 168.9 +/- 18.2 U/g，p < 0.01）。 DSS 治疗增强了 MMP2 和 MMP9 活性（>3 倍），而在接受 UCMSC 的小鼠中，MMP2 和 MMP9 活性显着降低。此外，在施用 UCMSC 后观察到 ER 应激相关蛋白的正向调节。结论：我们的结果表明 UCMSC 能够预防免疫缺陷小鼠中 DSS 诱导的结肠炎。使用这些小鼠，我们证明我们的 UCMSC 除了已知的 T 细胞免疫调节特性外，还具有直接的预防作用。此外，我们证明了 MMP 和 ER 应激在结肠炎形成中的关键功能，表明它们是 IBD 治疗的潜在治疗靶点。
Introduction: Inflammatory 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-Prkdc(scid)/J mice with particular attention to endoplasmic reticulum (ER) stress.Methods: UCMSCs were injected in NOD.CB17-Prkdc(scid)/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.Results: UCMSCs administration to immunodeficient NOD.CB17-Prkdc(scid)/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.Conclusions: Our 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.