title: Human bone marrow mesenchymal stem cell-derived hepatocytes express tissue inhibitor of metalloproteinases 4 and follistatin.
abstract: OBJECTIVE
  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.
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Jiaojiao
authors: J
authors: Xin
authors: Systems Biology Division, Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou, China.
authors: Wenchao
authors: W
authors: Ding
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Shaorui
authors: S
authors: Hao
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Longyan
authors: L
authors: Jiang
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Qian
authors: Q
authors: Zhou
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Tianzhou
authors: T
authors: Wu
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Dongyan
authors: D
authors: Shi
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Hongcui
authors: H
authors: Cao
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Lanjuan
authors: L
authors: Li
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Jun
authors: J
authors: Li
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D002681:China; D004195:Disease Models, Animal; D005260:Female; D038681:Follistatin / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D013552:Swine; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D015415:Biomarkers; D038681:Follistatin; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4
keywords: FST; Hepatocyte; TIMP-4; bone marrow mesenchymal stem cells