Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 18;10(1):98.
doi: 10.1186/s13287-019-1204-2.

Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway

Xiaoli Rong  1   2 , Junzhi Liu  3 , Xia Yao  4 , Tiechao Jiang  5 , Yimin Wang  6 , Feng Xie  7
Affiliations

Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway

Xiaoli Rong et al. Stem Cell Res Ther. .

Abstract

Background: Mesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis. Exosomes possess similar functions to their parent cells; however, they are safe and effective cell-free reagents with controllable and predictable outcomes. In this study, we investigated the therapeutic potential and underlying molecular mechanism for human bone mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) in the treatment of liver fibrosis.

Methods: We established an 8-week CCl4-induced rat liver fibrosis model, after which, we administered hBM-MSCs-Ex in vivo for 4 weeks. The resulting histopathology, liver function, and inflammatory cytokines were analyzed. In addition, we investigated the anti-fibrotic mechanism of hBM-MSCs-Ex in hepatic stellate cells (HSCs) and liver fibrosis tissue, by western blotting for the expression of Wnt/β-catenin signaling pathway-related genes.

Results: In vivo administration of hBM-MSCs-Ex effectively alleviated liver fibrosis, including a reduction in collagen accumulation, enhanced liver functionality, inhibition of inflammation, and increased hepatocyte regeneration. Moreover, based on measurement of the collagen area, Ishak fibrosis score, MDA levels, IL-1, and IL-6, the therapeutic effect of hBM-MSCs-Ex against liver fibrosis was significantly greater than that of hBM-MSCs. In addition, we found that hBM-MSCs-Ex inhibited the expression of Wnt/β-catenin pathway components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, Cyclin D1), α-SMA, and Collagen I, in both HSCs and liver fibrosis tissue.

Conclusions: These results suggest that hBM-MSCs-Ex treatment could ameliorate CCl4-induced liver fibrosis via inhibition of HSC activation through the Wnt/β-catenin pathway.

Keywords: Exosomes; Liver fibrosis; Wnt/β-catenin; hBM-MSCs.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

All experiments were performed in accordance with the guidelines and study protocols of the Animal Experiment Ethic Committee of Jilin University (Approval No. 201802072).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Exosome characterization. a Morphological appearance of cultured hBM-MSCs (bar = 100 μm). b Morphological analysis of hBM-MSCs-Ex by transmission electron microscopy (bar = 100 nm and 200 nm). c Size distribution measurements under flow conditions by nanoparticle tracking with the corresponding video frame. d Western blot assay indicated the positive expression of CD9, CD63, CD81, TSG101 and Alix proteins in hBM-MSCs-Ex
Fig. 2
Fig. 2
hBM-MSCs-Ex alleviates liver fibrosis in rats. a Study design. b Representative images showing the gross morphology and histological analysis of liver (scale bar = 1 mm), n = 12. c Collagen proportionate area quantification by computer-assisted image analysis at 4 weeks. d Ishak scoring criteria. e, f Quantitative analysis of hepatic Hyp and MDA content. **p < 0.01, ***p < 0.001. Data: n = 12; mean ± SD
Fig. 3
Fig. 3
hBM-MSCs-Ex improves liver function and decreases inflammation. a ALT, alanine aminotransferase. b AST, aspartate aminotransferase. c TP, total protein. d TBIL, total bilirubin. e ALP, alkaline phosphatase. f γ-GT, gamma glutamyl transpeptidase. g–l The relative inflammatory gene expression for IL-1, IL-2, IL-6, IL-8, IL-10, and TNF-α. *p < 0.05, **p < 0.01, ***p < 0.001. Data: n = 12; mean ± SD
Fig. 4
Fig. 4
hBM-MSCs-Ex increases Ki-67+ and decreases α-SMA+ in a rat model of liver fibrosis. a Photomicrographs of liver tissue sections showing IHC staining for α-SMA and Ki-67 (black arrows indicate brown-positive cells, bar = 1 mm). b–d Quantification of α-SMA and Ki-67-positive cells was performed by computer-assisted image analysis. **p < 0.01, ***p < 0.001. Data: n = 12; mean ± SD
Fig. 5
Fig. 5
hBM-MSCs-Ex inhibits the Wnt/β-catenin signaling pathway. a, c Representative western blotting analysis measuring PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, Cyclin D1, α-SMA, and Collagen I in HSCs and liver fibrosis tissue. b, d The quantification of protein relative intensity. ***p < 0.001, ***p < 0.001. Data, n = 3; mean ± SD
Fig. 6
Fig. 6
hBM-MSCs-Ex treatment alleviates liver fibrosis in both HSCs and liver fibrosis tissues through inhibition of Wnt/β-catenin signaling (PPARγ, Wnt3a, Wnt10b, β-catenin) and the downregulation of downstream gene expression (WISP1, Cyclin D1). This inhibits HSC activation to prevent further liver fibrosis
See this image and copyright information in PMC

References

    1. Kisseleva T, Brenner DA. Mechanisms of fibrogenesis. Exp Biol Med (Maywood) 2008;233(2):109–122. doi: 10.3181/0707-MR-190. - DOI - PubMed
    1. Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39(Suppl 1):S60–S63. doi: 10.1016/j.clinre.2015.06.015. - DOI - PMC - PubMed
    1. Venturi C, Sempoux C, Quinones JA, Bourdeaux C, Hoyos SP, Sokal E, Reding R. Dynamics of allograft fibrosis in pediatric liver transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2014;14(7):1648–1656. doi: 10.1111/ajt.12740. - DOI - PubMed
    1. Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med. 2015;30(5):580–589. doi: 10.3904/kjim.2015.30.5.580. - DOI - PMC - PubMed
    1. Liu WH, Song FQ, Ren LN, Guo WQ, Wang T, Feng YX, Tang LJ, Li K. The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases. J Cell Mol Med. 2015;19(3):511–520. doi: 10.1111/jcmm.12482. - DOI - PMC - PubMed

Publication types

MeSH terms