Long-Term Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Dextran Sulfate Sodium-Induced Murine Chronic Colitis

BACKGROUND/AIMS: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown beneficial effects in experimental colitis models, but the underlying mechanisms are not fully understood. We investigated the long-term effects of BM-MSCs, particularly in mice with chronic colitis. METHODS: Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in a series of three cycles. BM-MSCs were injected intravenously into DSS-treated mice three times during the first cycle. On day 33, the therapeutic effects were evaluated with clinicopathologic profiles and histological scoring. Inflammatory mediators were measured with real-time polymerase chain reaction. RESULTS: Systemic infusion of BM-MSCs ameliorated the severity of colitis, and body weight restoration was significantly promoted in the BM-MSC-treated mice. In addition, BM-MSC treatment showed a sustained beneficial effect throughout the three cycles. Microscopic examination revealed that the mice treated with BM-MSCs had fewer inflammatory infiltrates, a lesser extent of inflammation, and less crypt structure damage compared with mice with DSS-induced colitis. Anti-inflammatory cytokine levels of interleukin-10 were significantly increased in the inflamed colons of BM-MSC-treated mice compared with DSS-induced colitis mice. CONCLUSIONS: Systemic infusion of BM-MSCs at the onset of disease exerted preventive and rapid recovery effects, with long-term immunosuppressive action in mice with repeated DSS-induced chronic colitis.

THE ROLE OF REGULATED PROTEINS RELATED TO CELL CYCIE IN CARCINOGENESIS

The cell cycle is composed of G1, S, G2 and M phase. The transitions between different phases are regulated at checkpoint such as Start(restriction), S phase and mitotic checkpoint. These checkpoints are regulated by specific cyclins and Cdks(cyclin-dependent kinases). Especially, Start checkpoint in late G1 is though to be very important in control of cell cycle. In this study, it was shown various CDKN2(p16ink4A) alteration, including deletions, mutations, down regulations, and performed differential expression of p53, Cdk4, PCNA and pRb in stomach cancer tissues. 1. The frequency of CDKN2 mutations was not observed in the 19 primary stomach cancer tissues. In contrast to the mutations of CDKN2, mRNA levels was showed by Northern blot analysis that expression of CDKN2 was absent or decreased in 10 of the 19(53%) primary stomach adenocarcinoma. Western blot analysis was performed to determine the differential expression of p53, Cdk4, PCNA related to Start checkpoint. Overexpression of p53 was shown 38%, Cdk4 was expressed in all each specimens, and expression of PCNA was not shown. 2. As the other method to determine the differential expression of p53, Cdk4, PCNA and pRb, immunohistochemical analyses were performed on each 14 formalin-fixed and paraffin embedded tumor tissues of stomach adenocarcinoma. p53 overexpression was showed to clear nuclear staining only in tumor cells not in nonneoplastic cells. In staining for cdk4, the tumor was considered to be cdk4 positive if there was nuclear staining in tumor cells, regardless of cytoplasmic staining. PCNA staining for carcinoma tissues showed more intense nuclear staining in tumor cells than in nonneoplastic cells. pRb overexpression was show in tumor cells. Significant differences were observed in the expression of the proteins among the cancers from different anatomic site. Overexpression of adenocarcinomas had high rate of p53(57.1%) and pRb(71.4% ), and low late of cdk4(7.1% ) and PCNA(14.3% ), As these results, deletion of CDKN2 gene in human stomach cancer was not observed but mRNA expression was down regulated in restriction checkpoint, G1 phase. Inactivation of the CDKN2 gene due to hypermethylation may play an important role in development of cancer. And one of the abnormalities in p53, Cdk4, PCNA or pRb function occurs very common in various cancers, especially oral adenocarcinoma, osteosarcoma and squemous cell carcinoma, suggest that components in restriction checkpoint also play an critical role in the carcinogenesis and progression of cancers.