用于小鼠卡哈尔间质细胞的干细胞通过分泌前列腺素E2抑制细胞免疫和结肠炎。
Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion.
作者信息
Dave Maneesh, Hayashi Yujiro, Gajdos Gabriella B, Smyrk Thomas C, Svingen Phyllis A, Kvasha Sergiy M, Lorincz Andrea, Dong Haidong, Faubion William A, Ordog Tamas
机构信息
Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
出版信息
Gastroenterology. 2015 May;148(5):978-90. doi: 10.1053/j.gastro.2015.01.036. Epub 2015 Jan 28.
BACKGROUND & AIMS: After allogeneic transplantation, murine stem cells (SCs) for interstitial cells of Cajal (ICCs), electrical pacemaker, and neuromodulator cells of the gut, were incorporated into gastric ICC networks, indicating in vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSCs), which are emerging as potential therapeutic agents against autoimmune diseases, including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SCs could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways.
METHODS
Isolated ICC-SCs were studied by transcriptome profiling, cytokine assays, flow cytometry, mixed lymphocyte reaction, and T-cell proliferation assay. Mice with acute and chronic colitis induced by dextran sulfate sodium and T-cell transfer, respectively, were administered ICC-SCs intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging.
RESULTS
Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SCs preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SCs profoundly suppressed T-cell proliferation in vitro. Similar to MSCs, ICC-SCs strongly expressed cyclooxygenase 1/2 and basally secreted prostaglandin E2. Indomethacin, a cyclooxygenase inhibitor, countered the ICC-SC-mediated suppression of T-cell proliferation. In contrast, we found no role for regulatory T-cell-, programmed death receptor-, and transforming growth factor-β-mediated mechanisms reported in MSCs; and transcriptome profiling did not support a relationship between ICC-SCs and MSCs.
CONCLUSIONS
Murine ICC-SCs belong to a class different from MSCs and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression.
背景与目的
异体移植后，用于卡哈尔间质细胞（ICC）、肠道电起搏器和神经调节细胞的小鼠干细胞（SCs）被整合到胃ICC网络中，提示存在体内免疫抑制作用。免疫抑制是骨髓及其他非肠道来源的间充质干细胞（MSCs）的特征，这些细胞正成为治疗自身免疫性疾病（包括炎症性肠病）的潜在治疗药物。因此，我们研究了肠道来源的ICC-SCs是否也能减轻实验性结肠炎，并研究了ICC-SC介导的免疫抑制与MSC诱导途径相关的机制。
方法
通过转录组分析、细胞因子检测、流式细胞术、混合淋巴细胞反应和T细胞增殖试验对分离出的ICC-SCs进行研究。分别用葡聚糖硫酸钠和T细胞转移诱导急性和慢性结肠炎的小鼠腹腔注射ICC-SCs，并通过临床和病理评估来评价疾病活动度，通过活体成像评估ICC-SC的归巢情况。
结果
与品系匹配的真皮成纤维细胞不同，腹腔注射的ICC-SCs优先归巢至结肠，并通过临床和盲法病理评分降低了急性和慢性结肠炎的严重程度。ICC-SCs在体外能显著抑制T细胞增殖。与MSCs相似，ICC-SCs强烈表达环氧化酶1/2并基础分泌前列腺素E2。环氧化酶抑制剂吲哚美辛可对抗ICC-SC介导的T细胞增殖抑制作用。相比之下，我们未发现MSCs中报道的调节性T细胞、程序性死亡受体和转化生长因子-β介导的机制发挥作用；转录组分析也不支持ICC-SCs与MSCs之间存在关联。
结论
小鼠ICC-SCs属于不同于MSCs的一类细胞，并通过前列腺素E2介导的免疫抑制作用有效减轻实验性结肠炎。
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