Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets

Noriko Itaba, Yohei Kono, Kaori Watanabe, Tsuyoshi Yokobata, Hiroyuki Oka, Mitsuhiko Osaki, Hiroki Kakuta, Minoru Morimoto, Goshi Shiota

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Chronic hepatitis viral infection, alcoholic intoxication, and obesity cause liver fibrosis, which progresses to decompensated liver cirrhosis, a disease for which medical demands cannot be met. Since there are currently no approved anti-fibrotic therapies for established liver fibrosis, the development of novel modalities is required to improve patient prognosis. In this study, we clarified the anti-fibrotic effects of cell sheets produced from human bone marrow-derived mesenchymal stem cells (MSCs) incubated on a temperature-sensitive culture dish with the chemical compound IC-2. Orthotopic transplantation of IC-2-engineered MSC sheets (IC-2 sheets) remarkably reduced liver fibrosis induced by chronic CCl 4 administration. Further, the marked production of fibrolytic enzymes such as matrix metalloproteinase (MMP)-1 and MMP-14, as well as thioredoxin, which suppresses hepatic stellate cell activation, was observed in IC-2 sheets. Moreover, the anti-fibrotic effect of IC-2 sheets was much better than that of MSC sheets. Finally, knockdown experiments revealed that MMP-14 was primarily responsible for the reduction of liver fibrosis. Here, we show that IC-2 sheets could be a promising therapeutic option for established liver fibrosis.

Original languageEnglish
Article number6841
JournalScientific reports
Issue number1
Publication statusPublished - Dec 1 2019


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Cite this

Itaba, N., Kono, Y., Watanabe, K., Yokobata, T., Oka, H., Osaki, M., Kakuta, H., Morimoto, M., & Shiota, G. (2019). Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. Scientific reports, 9(1), [6841].