Human bone marrow mesenchymal stem cell (hBMSC) transplantation has been expected to be an alternative regenerative technique for liver diseases. However, the mechanism by which hBMSCs differentiate into hepatocytes is still unclear. Establishing the specific characteristics of hBMSC-derived hepatocytes (hBMSC-Heps) is critical for future clinical applications. In this study, potential hBMSC-Hep biomarkers were screened using cytokine arrays. Significant biomarkers were then validated by enzyme-linked immunosorbent assay (ELISA) in vitro and in vivo xenotransplantation model in fulminant hepatic failure (FHF) pigs. The results showed that 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 hours after hBMSC transplantation and reached their highest levels at 24 and 48 hours, 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, and transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation. TIMP-4 and FST represent potential novel biomarkers for characterising hBMSC-Heps and might be useful for future clinical applications.

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