Direct reprogramming of human fibroblasts to functional and expandable hepatocytes

Cell Stem Cell. 2014 Mar 6;14(3):370-84. doi: 10.1016/j.stem.2014.01.003. Epub 2014 Feb 27.


The generation of large numbers of functional human hepatocytes for cell-based approaches to liver disease is an important and unmet goal. Direct reprogramming of fibroblasts to hepatic lineages could offer a solution to this problem but so far has only been achieved with mouse cells. Here, we generated human induced hepatocytes (hiHeps) from fibroblasts by lentiviral expression of FOXA3, HNF1A, and HNF4A. hiHeps express hepatic gene programs, can be expanded in vitro, and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Upon transplantation into mice with concanavalin-A-induced acute liver failure and fatal metabolic liver disease due to fumarylacetoacetate dehydrolase (Fah) deficiency, hiHeps restore the liver function and prolong survival. Collectively, our results demonstrate successful lineage conversion of nonhepatic human cells into mature hepatocytes with potential for biomedical and pharmaceutical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, Polyomavirus Transforming / metabolism
  • Biliary Tract / metabolism
  • Cell Differentiation / genetics
  • Cell Lineage
  • Cell Proliferation
  • Cellular Reprogramming*
  • Concanavalin A
  • Fetus / cytology
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Hepatocytes / cytology*
  • Hepatocytes / metabolism
  • Hepatocytes / transplantation
  • Humans
  • Hydrolases / deficiency
  • Hydrolases / metabolism
  • Inactivation, Metabolic
  • Liver Failure / pathology
  • Liver Failure / therapy
  • Mice
  • Mice, Inbred C57BL
  • Stem Cells / cytology
  • Stem Cells / metabolism


  • Antigens, Polyomavirus Transforming
  • Concanavalin A
  • Hydrolases
  • fumarylacetoacetase