Effect of function-enhanced mesenchymal stem cells infected with decorin-expressing adenovirus on hepatic fibrosis

Yoon Ok Jang, Meeyon Cho, Chae Ok Yun, Soonkoo Baik, Kyusang Park, Seungkuy Cha, Sei Jin Chang, Moonyoung Kim, Yoo Li Lim, Sang Ok Kwon

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are known to have an antifibrotic effect and could be used as vehicles for targeted gene delivery. Decorin plays a protective role against fibrogenesis by modulating the degradation of the extracellular matrix. The aim of this study was to determine whether the antifibrotic effect of a combination treatment consisting of BM-MSCs and decorin on hepatic fibrosis is superior to BM-MSCs alone. The effects of BM-MSCs infected with decorin-expressing adenovirus (DCN-MSCs) on hepatic fibrosis were examined in a rat model of thioacetamide (TAA)-induced cirrhosis. The effects of infection with decorin-expressing adenovirus and of incubation with the conditioned medium of DCN-MSCs on transforming growth factor-β (TGF-β) signaling were analyzed in immortalized human hepatic stellate cells (HSCs). According to the Laennec fibrosis scoring system, cirrhotic livers from rats treated with DCN-MSCs exhibited histological improvement compared with cirrhotic livers from rats treated with control adenovirus-infected MSCs (CA-MSCs). DCN-MSC treatment reduced hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with DCN-MSCs than with CA-MSCs. The upregulation of collagen-1, α-smooth muscle actin (α-SMA), TGF-β1, and Smad3 phosphorylation in cirrhotic livers was prevented by DCN-MSC administration. Intriguingly, medium from cultured DCN-MSCs blocked both Smad3 phosphorylation and exogenous TGF-β1 stimulated α-SMA synthesis in HSCs. DCN-MSCs exert strong protective effects against hepatic fibrosis by suppressing TGF-β/Smad signaling. Thus, treatment with DCN-MSCs is a potentially novel and efficient therapeutic approach for patients with intractable cirrhosis.

Original languageEnglish
Pages (from-to)1247-1256
Number of pages10
JournalStem Cells Translational Medicine
Volume5
Issue number9
DOIs
Publication statusPublished - 2016 Jan 1

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Decorin
Mesenchymal Stromal Cells
Adenoviridae
Fibrosis
Liver
Transforming Growth Factors
Bone Marrow
Thioacetamide
Hepatic Stellate Cells
Collagen
Phosphorylation
Hydroxyproline
Therapeutics
Conditioned Culture Medium
Extracellular Matrix
Smooth Muscle
Actins
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Developmental Biology
  • Cell Biology

Cite this

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title = "Effect of function-enhanced mesenchymal stem cells infected with decorin-expressing adenovirus on hepatic fibrosis",
abstract = "Bone marrow-derived mesenchymal stem cells (BM-MSCs) are known to have an antifibrotic effect and could be used as vehicles for targeted gene delivery. Decorin plays a protective role against fibrogenesis by modulating the degradation of the extracellular matrix. The aim of this study was to determine whether the antifibrotic effect of a combination treatment consisting of BM-MSCs and decorin on hepatic fibrosis is superior to BM-MSCs alone. The effects of BM-MSCs infected with decorin-expressing adenovirus (DCN-MSCs) on hepatic fibrosis were examined in a rat model of thioacetamide (TAA)-induced cirrhosis. The effects of infection with decorin-expressing adenovirus and of incubation with the conditioned medium of DCN-MSCs on transforming growth factor-β (TGF-β) signaling were analyzed in immortalized human hepatic stellate cells (HSCs). According to the Laennec fibrosis scoring system, cirrhotic livers from rats treated with DCN-MSCs exhibited histological improvement compared with cirrhotic livers from rats treated with control adenovirus-infected MSCs (CA-MSCs). DCN-MSC treatment reduced hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with DCN-MSCs than with CA-MSCs. The upregulation of collagen-1, α-smooth muscle actin (α-SMA), TGF-β1, and Smad3 phosphorylation in cirrhotic livers was prevented by DCN-MSC administration. Intriguingly, medium from cultured DCN-MSCs blocked both Smad3 phosphorylation and exogenous TGF-β1 stimulated α-SMA synthesis in HSCs. DCN-MSCs exert strong protective effects against hepatic fibrosis by suppressing TGF-β/Smad signaling. Thus, treatment with DCN-MSCs is a potentially novel and efficient therapeutic approach for patients with intractable cirrhosis.",
author = "Jang, {Yoon Ok} and Meeyon Cho and Yun, {Chae Ok} and Soonkoo Baik and Kyusang Park and Seungkuy Cha and Chang, {Sei Jin} and Moonyoung Kim and Lim, {Yoo Li} and Kwon, {Sang Ok}",
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Effect of function-enhanced mesenchymal stem cells infected with decorin-expressing adenovirus on hepatic fibrosis. / Jang, Yoon Ok; Cho, Meeyon; Yun, Chae Ok; Baik, Soonkoo; Park, Kyusang; Cha, Seungkuy; Chang, Sei Jin; Kim, Moonyoung; Lim, Yoo Li; Kwon, Sang Ok.

In: Stem Cells Translational Medicine, Vol. 5, No. 9, 01.01.2016, p. 1247-1256.

Research output: Contribution to journalArticle

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AU - Jang, Yoon Ok

AU - Cho, Meeyon

AU - Yun, Chae Ok

AU - Baik, Soonkoo

AU - Park, Kyusang

AU - Cha, Seungkuy

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AU - Kim, Moonyoung

AU - Lim, Yoo Li

AU - Kwon, Sang Ok

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N2 - Bone marrow-derived mesenchymal stem cells (BM-MSCs) are known to have an antifibrotic effect and could be used as vehicles for targeted gene delivery. Decorin plays a protective role against fibrogenesis by modulating the degradation of the extracellular matrix. The aim of this study was to determine whether the antifibrotic effect of a combination treatment consisting of BM-MSCs and decorin on hepatic fibrosis is superior to BM-MSCs alone. The effects of BM-MSCs infected with decorin-expressing adenovirus (DCN-MSCs) on hepatic fibrosis were examined in a rat model of thioacetamide (TAA)-induced cirrhosis. The effects of infection with decorin-expressing adenovirus and of incubation with the conditioned medium of DCN-MSCs on transforming growth factor-β (TGF-β) signaling were analyzed in immortalized human hepatic stellate cells (HSCs). According to the Laennec fibrosis scoring system, cirrhotic livers from rats treated with DCN-MSCs exhibited histological improvement compared with cirrhotic livers from rats treated with control adenovirus-infected MSCs (CA-MSCs). DCN-MSC treatment reduced hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with DCN-MSCs than with CA-MSCs. The upregulation of collagen-1, α-smooth muscle actin (α-SMA), TGF-β1, and Smad3 phosphorylation in cirrhotic livers was prevented by DCN-MSC administration. Intriguingly, medium from cultured DCN-MSCs blocked both Smad3 phosphorylation and exogenous TGF-β1 stimulated α-SMA synthesis in HSCs. DCN-MSCs exert strong protective effects against hepatic fibrosis by suppressing TGF-β/Smad signaling. Thus, treatment with DCN-MSCs is a potentially novel and efficient therapeutic approach for patients with intractable cirrhosis.

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