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Therapeutic strategy for intractable inflammatory bowel diseases by mesenchymal stem cells

间充质干细胞治疗难治性炎症性肠病的策略

基本信息

批准号：
15590675
负责人：
ARAKAWA Tetsuo
金额：
$ 1.98万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Bone marrow-derived cells including a small amount of mesenchymal stem cells (MSCs) had therapeutic effects for clinical human and experimental animal colitis. Its detailed mechanism(s) may be partly mediated by mucosal regeneration, since MSCs have potential for differentiation to several parts of cells. But MSCs was thought to have other functions such as anti-inflammation as well as mucosal regeneration, because anti-inflammatory system is involved in the repair of colitis. We examined the therapeutic efficacy and anti-inflammatory effects of bone marrow-derived MSCs for dextran sulfate sodium (DSS)-induced acute colitis in rats. Experimental colitis was induced by orally administration of 0, 1, 2, or 4% DSS in drinking water for 7 days in inbred male Lewis rats. Bone marrow was extruded from tibias and femurs. Then, its mononuclear cells were isolated and cultured in low-glucose DMEM containing 10% fetal bovine serum for MSCs outgrowth. On 0, 2, and 4 days after the administration … More of DSS, MSCs (5 X 10^6 cells) were injected via tail vein. We checked the volumes of food and water intake, stool condition, and body weight everyday. On day 7, total colon was excised and each colonic mRNA expression of inflammatory cytokines such as TNF-α, IL-1β, IL-10, and COX2 was measured by real time RT-PCR method. We confirmed the MSC's characterization by both the immunostaining for vimentin and α-smooth muscle actin and the cell surface markers such as CD90, the bone marrow progenitor cell marker, but not CD45, HLA-DR, CD11b, nor CD31 using flow cytometric technique. Optimal dose of DSS for the rats used was confirmed at 4% by the assessing for loss of body weight and appetite, bloody fluid stool, and the shortening of colon length. MSC treatment improved the bloody stool and body weight loss, and significantly inhibited the shortening of colon length. At the rectum of MSC-treated rats, expressions of local inflammatory cytokines such as TNF-α and IL-1β were markedly decreased to about 40 and 15%. Local COX2 expression was also suppressed to 15%. IL-10, an anti-inflammatory cytokine, expression was also, decreased to 25%. At the distal colon cite (slightly oral side of rectum), similar tendency was observed about the expressions of cytokines in the MSC-treated colons. These findings suggested that MSC could have the therapeutic efficacy for the experimental colitis via anti-inflammatory functions. Less

骨髓来源的细胞包括少量的间充质干细胞（MSCs）对临床人类和实验动物结肠炎具有治疗作用。其详细机制可能部分由粘膜再生介导，因为MSC具有分化为细胞的几个部分的潜力。但由于抗炎系统参与了结肠炎的修复过程，因此MSC被认为具有抗炎和粘膜再生等功能。我们研究了骨髓来源的MSC对葡聚糖硫酸钠（DSS）诱导的大鼠急性结肠炎的治疗效果和抗炎作用。在近交系雄性刘易斯大鼠中，通过口服给予含0、1、2或4% DSS的饮用水7天诱导实验性结肠炎。骨髓从胫骨和股骨中挤出。分离其单个核细胞，在含10%胎牛血清的低糖DMEM培养基中培养，以促进MSCs的生长。给药后0、2和4天 ...更多信息的DSS，通过尾静脉注射MSC（5 X 10^6个细胞）。每天检查进食量、饮水量、大便情况和体重。第7天，切除全结肠，通过真实的时间RT-PCR方法检测每个结肠炎性细胞因子如TNF-α、IL-1β、IL-10和COX 2的mRNA表达。流式细胞术检测波形蛋白、α-平滑肌肌动蛋白和细胞表面标志物CD 90，而未检测到CD 45、HLA-DR、CD 11b和CD 31。通过评估体重和食欲下降、血便和结肠长度缩短，确定所用大鼠的DSS最佳剂量为4%。MSC治疗改善了血便和体重减轻，并显著抑制了结肠长度缩短。在MSC处理的大鼠直肠，局部炎性细胞因子如TNF-α和IL-1β的表达显著降低至约40%和15%。局部COX 2表达也被抑制至15%。抗炎细胞因子IL-10的表达也降低至25%。在远端结肠部位（直肠稍靠口侧），MSC处理的结肠中细胞因子的表达也观察到类似的趋势。这些结果表明，MSC可能通过抗炎作用对实验性结肠炎具有治疗作用。少

项目成果

期刊论文数量（48）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach.

吲哚美辛（而非幽门螺杆菌）抑制离体豚鼠胃的适应性松弛。

DOI：
发表时间：
2004
期刊：
Drugs Exp Clin Res. 30(5-6)
影响因子：
0
作者：
Suto R;Tominaga K;Mizuguchi H;Sasaki E;Higuchi K;Kim S;Iwao H;Arakawa T;Fujiwara Y et al.;Arakawa T et al.;Watanabe T et al.;Yamamori K et al.;Tominaga K et al.;Higuchi K et al.
通讯作者：
Higuchi K et al.

Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chromic reflux esophagitis.

大鼠铬反流性食管炎中转化生长因子-α和表皮生长因子受体的表达增加。

DOI：
发表时间：
2004
期刊：
J Gastroenterol Hepatol. 19(5)
影响因子：
0
作者：
Suto R;Tominaga K;Mizuguchi H;Sasaki E;Higuchi K;Kim S;Iwao H;Arakawa T;Fujiwara Y et al.
通讯作者：
Fujiwara Y et al.

Monocyte chemotactic protein-1 regulates leukocyte recruitment during gastric ulcer recurrence induced by tumor necrosis factor-alpha.

单核细胞趋化蛋白-1 在肿瘤坏死因子-α 诱导的胃溃疡复发过程中调节白细胞募集。

DOI：
发表时间：
2004
期刊：
Am J Physiol Gastrointest Liver Physiol. 287(4)
影响因子：
0
作者：
Watanabe T;Higuchi K;Hamaguchi M;Shiba M;Tominaga K;Fujiwara Y;Matsumoto T;Arakawa T
通讯作者：
Arakawa T

Suto R et al.: "Dominant-negative mutant of c-Jun gene transfer : a novel therapeutic strategy for colorectal cancer"Gene Ther. 11. 187-193 (2004)

Suto R 等人：“c-Jun 基因转移的显性失活突变体：结直肠癌的新型治疗策略”Gene Ther。