Human bone marrow mesenchymal stem cell-derived hepatocytes express tissue inhibitor of metalloproteinases 4 and follistatin

Liver Int. 2015 Oct;35(10):2301-10. doi: 10.1111/liv.12797. Epub 2015 Feb 17.


Background & aims: Human bone marrow mesenchymal stem cell (hBMSC) transplantation is expected to become an alternative regenerative technique for liver diseases. However, the mechanism by which hBMSCs differentiate into hepatocytes is still unclear. The aim of this study was to establish the specific characteristics of hBMSC-derived hepatocytes (hBMSC-Heps) for future clinical applications.

Methods: Potential hBMSC-Hep biomarkers were screened using cytokine arrays. Significant biomarkers were then validated by enzyme-linked immunosorbent assay (ELISA) in vitro and in an in vivo xenotransplantation model in fulminant hepatic failure (FHF) pigs.

Results: After 20 days of differentiation, the expression levels of tissue inhibitor of metalloproteinases 4 (TIMP-4) and follistatin (FST) in functional hBMSC-Heps were significantly increased, whereas those of activin A, osteoprotegerin and platelet-derived growth factor α polypeptide (PDGF-A) were significantly decreased. The high levels of TIMP-4 and FST were validated by ELISA in hBMSC-Heps grown in differentiation medium. The in vivo xenotransplantation model in FHF pigs showed that the serum levels of TIMP-4 and FST were significantly increased 6 h after hBMSC transplantation and reached their highest levels at 24 and 48 h, respectively, after hBMSC transplantation. Immunohistochemistry confirmed that TIMP-4 and FST were expressed in cultured hBMSC-Heps and in implanted hBMSC-Heps in pig livers.

Conclusions: The transdifferentiation of hBMSCs into hepatocytes is associated with the expression of TIMP-4 and FST. TIMP-4 and FST represent potential novel biomarkers for the characterisation of hBMSC-Heps and may be useful for future clinical applications.

Keywords: FST; Hepatocyte; TIMP-4; bone marrow mesenchymal stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Cell Differentiation
  • Cell Transdifferentiation
  • Cells, Cultured
  • China
  • Disease Models, Animal
  • Female
  • Follistatin / genetics
  • Follistatin / metabolism*
  • Hepatocytes / metabolism
  • Humans
  • Liver Failure, Acute / chemically induced
  • Liver Failure, Acute / therapy*
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells
  • Swine
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism*
  • Transplantation, Heterologous


  • Biomarkers
  • Follistatin
  • Tissue Inhibitor of Metalloproteinases
  • tissue inhibitor of metalloproteinase-4