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

  • Deniz Guney DumanEmail author
  • Noushin Zibandeh
  • Mustafa Umit Ugurlu
  • Cigdem Celikel
  • Tolga Akkoc
  • Munkhtsetseg Banzragch
  • Deniz Genc
  • Osman Ozdogan
  • Tunç Akkoc
Original Article


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.


Cell therapy Stem cells Animal models Natural killer cells 


NK cells

Natural killer cells


Mesenchymal stem cells


Bone marrow


Common bile duct


Common bile duct ligated




Tumor necrosis factor




Autologous bone marrow cell infusion


Hepatic stellate cells


Aspartate aminotransferase


Alanine aminotransferase


Blood urea nitrogen


Phosphate buffer saline


Dulbecco’s modified Eagle medium


Fetal bovine serum


Green fluorescent protein


Carboxyfluorescein succinimidyl ester


Hepatocytes growth factor


Matrix metalloproteinases


Cytokine signaling 1

Treg cells

T regulatory cells



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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest regarding the publication of this article.

Supplementary material

11033_2019_4736_MOESM1_ESM.tif (53 kb)
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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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology, School of MedicineMarmara UniversityIstanbulTurkey
  2. 2.Department of Pediatric Allergy-Immunology, School of MedicineMarmara UniversityIstanbulTurkey
  3. 3.Department of General Surgery, School of MedicineMarmara UniversityIstanbulTurkey
  4. 4.Department of Pathology, School of MedicineMarmara UniversityIstanbulTurkey
  5. 5.Genetic Engineering and Biotechnology InstituteTubitak Marmara Research CenterKocaeliTurkey
  6. 6.Department of GastroenterologyDarica Farabi State HospitalKocaeliTurkey
  7. 7.Department of GastroenterologyMarmara University Pendik Education and Research HospitalIstanbulTurkey

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