Therapeutic strategy for intractable inflammatory bowel diseases by mesenchymal stem cells

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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