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Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model

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Abstract

Natural killer (NK) cells have antifibrotic effects. We have evaluated the influence of rat bone marrow-mesenchymal stem cell (BM-MSC) treatment on liver histology, biochemical liver function tests, systemic immunoregulatory state and NK cell distribution in liver and peripheral blood in rat model of common bile duct (CBD) ligation and compared the results with the control group. Rats were divided into three groups: (1) CBD ligated (CBDL) rats received phosphate-buffered saline (CBDL + PBS group) or (2) MSC (CBDL + MSC group) and sham-operated rats received MSC (healthy + MSC group). We found significantly decreased fibrosis scores with BM-MSC treatment in CBDL rats compared to the control (CBDL + PBS) group while no fibrosis developed in sham operated (healthy + MSC) group. BM-MSC treatment has decreased the inflammation as reflected by the significantly decreased T cell proliferation and inflammatory cytokine concentrations from splenocyte culture and liver tissue itself compared to CBDL + PBS. NK cells both in parenchyme and portal areas decreased significantly in liver and blood in CBDL + PBS compared to healthy + MSC while they were found to be increased in CBDL + MSC compared to CBDL + PBS rats. In conclusion, BM-MSCs may suppress hepatic fibrosis accompanied by expanded intrahepatic NK cells in CBDL rats. Thus, our animal study shows that MSC treatment holds great promise for treatment of patients with end-stage liver diseases through a possible mechanism by adopting the NK cell population and new studies investigating the role of NK cells and clinical fibrosis are warranted.

Trial registration number: Marmara University Animal Care and Use Committee approval code: 73.2013.mar.

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Abbreviations

NK cells:

Natural killer cells

MSC:

Mesenchymal stem cells

BM:

Bone marrow

CBD:

Common bile duct

CBDL:

Common bile duct ligated

IL:

Interleukin

TNF:

Tumor necrosis factor

IFN-γ:

Interferon-γ

ABMI:

Autologous bone marrow cell infusion

HSCs:

Hepatic stellate cells

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

BUN:

Blood urea nitrogen

PBS:

Phosphate buffer saline

DMEM:

Dulbecco’s modified Eagle medium

FBS:

Fetal bovine serum

GFP:

Green fluorescent protein

CFSE:

Carboxyfluorescein succinimidyl ester

HGF:

Hepatocytes growth factor

MMPs:

Matrix metalloproteinases

SOCS1:

Cytokine signaling 1

Treg cells:

T regulatory cells

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Acknowledgements

This study was funded by the grant (SAG-A-041213-0443) from Marmara University Scientific Research Project Commission.

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Authors and Affiliations

  1. Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey

    Deniz Guney Duman & Osman Ozdogan

  2. Department of Pediatric Allergy-Immunology, School of Medicine, Marmara University, Istanbul, Turkey

    Noushin Zibandeh, Deniz Genc & Tunç Akkoc

  3. Department of General Surgery, School of Medicine, Marmara University, Istanbul, Turkey

    Mustafa Umit Ugurlu

  4. Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey

    Cigdem Celikel

  5. Genetic Engineering and Biotechnology Institute, Tubitak Marmara Research Center, Kocaeli, Turkey

    Tolga Akkoc

  6. Department of Gastroenterology, Darica Farabi State Hospital, Kocaeli, Turkey

    Munkhtsetseg Banzragch

  7. Department of Gastroenterology, Marmara University Pendik Education and Research Hospital, Ust Kaynarca, Pendik, 34899, Istanbul, Turkey

    Deniz Guney Duman

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  1. Deniz Guney Duman
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  2. Noushin Zibandeh
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  4. Cigdem Celikel
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  7. Deniz Genc
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  9. Tunç Akkoc
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Correspondence to Deniz Guney Duman.

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11033_2019_4736_MOESM1_ESM.tif

Supplementary material Scheme of study protocol. Fibrosis was induced by common bile duct ligation which was taken as time zero. On day 14, MSCs (1 × 106) were injected through tail vein. Rats were sacrificed on day 28 (TIF 53 KB)

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Duman, D.G., Zibandeh, N., Ugurlu, M.U. et al. Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model. Mol Biol Rep 46, 2997–3008 (2019). https://doi.org/10.1007/s11033-019-04736-4

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  • DOI: https://doi.org/10.1007/s11033-019-04736-4

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