title: Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes.
abstract: Considerable progress has been made in developing antifibrotic agents and other strategies to treat liver fibrosis; however, significant long-term restoration of functional liver mass has not yet been achieved. Therefore, we investigated whether transplanted hepatic stem/progenitor cells can effectively repopulate the liver with advanced fibrosis/cirrhosis. Stem/progenitor cells derived from fetal livers or mature hepatocytes from DPPIV(+) F344 rats were transplanted into DPPIV(-) rats with thioacetamide (TAA)-induced fibrosis/cirrhosis; rats were sacrificed 1, 2, or 4 months later. Liver tissues were analyzed by histochemistry, hydroxyproline determination, reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. After chronic TAA administration, DPPIV(-) F344 rats exhibited progressive fibrosis, cirrhosis, and severe hepatocyte damage. Besides stellate cell activation, increased numbers of stem/progenitor cells (Dlk-1(+), AFP(+), CD133(+), Sox-9(+), FoxJ1(+)) were observed. In conjunction with partial hepatectomy (PH), transplanted stem/progenitor cells engrafted, proliferated competitively compared to host hepatocytes, differentiated into hepatocytic and biliary epithelial cells, and generated new liver mass with extensive long-term liver repopulation (40.8 ± 10.3%). Remarkably, more than 20% liver repopulation was achieved in the absence of PH, associated with reduced fibrogenic activity (e.g., expression of alpha smooth muscle actin, platelet-derived growth factor receptor β, desmin, vimentin, tissue inhibitor of metalloproteinase-1) and fibrosis (reduced collagen). Furthermore, hepatocytes can also replace liver mass with advanced fibrosis/cirrhosis, but to a lesser extent than fetal liver stem/progenitor cells.
  
  
  CONCLUSIONS
  This study is a proof of principle demonstration that transplanted epithelial stem/progenitor cells can restore injured parenchyma in a liver environment with advanced fibrosis/cirrhosis and exhibit antifibrotic effects.
authors.affiliation: Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, New York, NY; Department of Medicine (Division of Gastroenterology and Liver Diseases), Albert Einstein College of Medicine of Yeshiva University, New York, NY.
authors.forename: Mladen I
authors.initials: MI
authors.lastname: Yovchev
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Xue
authors.forename: David A
authors.initials: DA
authors.lastname: Shafritz
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.forename: Michael
authors.initials: M
authors.lastname: Oertel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D053686:Fetal Stem Cells / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000196:embryology / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008115:Liver Regeneration; D008297:Male; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D033581:Stem Cell Transplantation; D013853:Thioacetamide
chemical_list: D013853:Thioacetamide