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Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes
Author(s) -
Yovchev Mladen I.,
Xue Yuhua,
Shafritz David A.,
Locker Joseph,
Oertel Michael
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26615
Subject(s) - progenitor cell , stem cell , repopulation , liver regeneration , hepatocyte , progenitor , cancer research , liver cytology , pathology , biology , medicine , microbiology and biotechnology , regeneration (biology) , haematopoiesis , liver metabolism , in vitro , biochemistry
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. Conclusion : 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. (H epatology 2014;58:284–295)