Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury

• Published in: International journal of molecular sciences Vol. 15; no. 4; pp. 7004 - 7028
• Main Authors: Stock, Peggy, Brückner, Sandra, Winkler, Sandra, Dollinger, Matthias M, Christ, Bruno
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22-04-2014; Molecular Diversity Preservation International (MDPI)
• Subjects: Acetaminophen - toxicity; acute liver injury; Animals; Aspartate Aminotransferases - blood; Bone marrow; Bone Marrow Cells - cytology; Cell Differentiation; Cell growth; cell transplantation; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - therapy; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; hepatocyte differentiation; Hepatocytes - cytology; Hepatocytes - transplantation; human mesenchymal stem cells; Humans; Liver diseases; Liver Regeneration; Male; Mesenchymal Stromal Cells - cytology; Mice; stem cell-derived hepatocytes; Stem cells; Time Factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms15047004

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.