Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury.
Mesenchymal stem cells from human bone marrow (hMSC) have the potential to differentiate into hepatocyte-like cells in vitro and continue to maintain important hepatocyte functions in vivo after transplantation into host mouse livers. Here, hMSC were differentiated into hepatocyte-like cells in vitro (hMSC-HC) and transplanted into livers of immunodeficient Pfp/Rag2⁻/⁻ mice treated with a sublethal dose of acetaminophen (APAP) to induce acute liver injury. APAP induced a time- and dose-dependent damage of perivenous areas of the liver lobule. Serum levels of aspartate aminotransferase (AST) increased to similar levels irrespective of hMSC-HC transplantation. Yet, hMSC-HC resided in the damaged perivenous areas of the liver lobules short-term preventing apoptosis and thus progress of organ destruction. Disturbance of metabolic protein expression was lower in the livers receiving hMSC-HC. Seven weeks after APAP treatment, hepatic injury had completely recovered in groups both with and without hMSC-HC. Clusters of transplanted cells appeared predominantly in the periportal portion of the liver lobule and secreted human albumin featuring a prominent quality of differentiated hepatocytes. Thus, hMSC-HC attenuated the inflammatory response and supported liver regeneration after acute injury induced by acetaminophen. They hence may serve as a novel source of hepatocyte-like cells suitable for cell therapy of acute liver diseases.
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany. peggy.stock@medizin.uni-leipzig.de.
Peggy
P
Stock
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany. sandra.brueckner@medizin.uni-leipzig.de.
Sandra
S
Brückner
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany. sandra.winkler@medizin.uni-leipzig.de.
Sandra
S
Winkler
Clinics for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. matthias.dollinger@uniklinik-ulm.de.
Matthias M
MM
Dollinger
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany. bruno.christ@medizin.uni-leipzig.de.
Bruno
B
Christ
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000628:therapy*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D008115:Liver Regeneration; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D013997:Time Factors
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D000082:Acetaminophen; D001219:Aspartate Aminotransferases