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

Research output: Contribution to journalArticle

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Abstract

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
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Mesenchymal Stromal Cells
Liver Cirrhosis
Matrix Metalloproteinase 14
Hepatic Stellate Cells
Alcoholic Intoxication
Matrix Metalloproteinase 1
Thioredoxins
Virus Diseases
Chronic Hepatitis
Obesity
Transplantation
Bone Marrow
Temperature
Enzymes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Itaba, N., Kono, Y., Watanabe, K., Yokobata, T., Oka, H., Osaki, M., ... Shiota, G. (2019). Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. Scientific reports, 9(1), [6841]. https://doi.org/10.1038/s41598-019-43298-0

Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. / Itaba, Noriko; Kono, Yohei; Watanabe, Kaori; Yokobata, Tsuyoshi; Oka, Hiroyuki; Osaki, Mitsuhiko; Kakuta, Hiroki; Morimoto, Minoru; Shiota, Goshi.

In: Scientific reports, Vol. 9, No. 1, 6841, 01.12.2019.

Research output: Contribution to journalArticle

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, vol. 9, no. 1, 6841. https://doi.org/10.1038/s41598-019-43298-0
Itaba, Noriko ; Kono, Yohei ; Watanabe, Kaori ; Yokobata, Tsuyoshi ; Oka, Hiroyuki ; Osaki, Mitsuhiko ; Kakuta, Hiroki ; Morimoto, Minoru ; Shiota, Goshi. / Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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