Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion.
Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion.
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DOI：
10.1053/j.gastro.2015.01.036
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发表时间：
2015-05
期刊：
影响因子：
29.4
通讯作者：
Ordog T
中科院分区：
文献类型：
--
作者：
Dave M;Hayashi Y;Gajdos GB;Smyrk TC;Svingen PA;Kvasha SM;Lorincz A;Dong H;Faubion WA Jr;Ordog T
同种异体移植后，Cajal间质细胞（ICC）的鼠干细胞（SC），肠道的电起搏器和神经调节细胞，纳入胃ICC网络，表明体内免疫抑制。免疫抑制是骨髓和其他非肠源性间充质干细胞（MSC）的特征，其正在成为对抗自身免疫性疾病（包括炎症性肠病）的潜在治疗剂。因此，我们研究了肠源性ICC-SC是否也可以减轻实验性结肠炎，并研究了ICC-SC介导的免疫抑制与MSC诱导途径相关的机制。通过转录组分析、细胞因子测定、流式细胞术、混合淋巴细胞反应和T细胞增殖测定对分离的ICC-SC进行研究。分别通过葡聚糖硫酸钠和T细胞转移诱导的急性和慢性结肠炎小鼠腹腔内给予ICC-SC，并通过临床和病理学评估评估疾病活动性，并通过实时成像评估ICC-SC归巢。与菌株匹配的真皮成纤维细胞不同，腹腔内施用的ICC-SC优先归巢至结肠，并通过临床和盲法病理评分评估降低急性和慢性结肠炎的严重程度。ICC-SC在体外显著抑制T细胞增殖。与MSC相似，ICC-SC强烈表达环氧合酶1/2，并基本分泌前列腺素E2。吲哚美辛，环氧合酶抑制剂，反击ICC-SC介导的抑制T细胞增殖。相比之下，我们发现MSC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介导的机制没有作用;转录组分析不支持ICC-SC和MSC之间的关系。小鼠ICC-SC属于不同于MSC的类别，并且通过前列腺素E2介导的免疫抑制有效地减轻实验性结肠炎。
Following allogeneic transplantation, murine stem cells (SC) for interstitial cells of Cajal (ICC), electrical pacemaker and neuromodulator cells of the gut, incorporated into gastric ICC networks indicating in-vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSC), which are emerging as potential therapeutic agents against autoimmune diseases including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SC could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways. Isolated ICC-SC 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-SC intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging. Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SC preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SC profoundly suppressed T cell proliferation in vitro. Similarly to MSC, ICC-SC 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 MSC; and transcriptome profiling did not support a relationship between ICC-SC and MSC. Murine ICC-SC belong to a class different from MSC and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression.
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