Human Bone Marrow Mesenchymal Stem Cell-Derived Hepatocytes Improve the Mouse Liver after Acute Acetaminophen Intoxication by Preventing Progress of Injury

Abstract

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.

Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration—Systematic Review of the Literature Focused on Experimental Studies in Rodent Models

“…In regard to ADSCs commitment rate, which is an issue of crucial importance, ADSCs are committed at higher rates in hepatic lineage (compared to BM-MSCs) after pretreatment with growth factors in order to differentiate into hepatic-like cells [13, 54, 55]. Stimulants such as HGF, EGF, and FGF can influence primary steps of ADSCs differentiation while oncostatin M (OSM) plays a pivotal role in further maturation and expression of hepatocytes properties [56–58, 60].…”

“…These features enhanced liver regeneration (LG) in acute and chronic liver pathologies in rodents. Furthermore, MSCs improved LG by presenting proproliferative and antiapoptotic properties, thus hampering disease progress [11–13]. These proregenerative properties of MSCs might also enhance the regenerative capacity of the remaining liver after extensive resection [14].…”

Pathological implications of cadherin zonation in mouse liver

“…Acute liver injury was induced by acetaminophen [32] and chronic liver injury (NASH) by feeding a methioninecholine-deficient (MCD) diet [29] in immune-deficient Pfp/ Rag2 -/-mice. DPPIV -/-mice at the age of 12-14 weeks underwent partial hepatectomy and were sacrificed 48 h after surgery as described before [38].…”

“…The disease may progress to fibrosis, cirrhosis, and end-stage liver disease [23] associated with an increased risk of cardiovascular mortality, type 2 diabetes mellitus and obesity [24][25][26] carrying gender and ethnological variability [27]. The etiology of chronic and acute liver injury has been studied in numerous animal models unraveling the underlying mechanisms specific for the different liver injuries like NASH [28,29], and a1-antitrypsin deficiency [30,31] as prominent examples of chronic liver disease and acetaminophen-(APAP-) induced ALF [32,33] and partial hepatectomy [34] as models for acute liver injury.…”

Attenuation of Postoperative Acute Liver Failure by Mesenchymal Stem Cell Treatment Due to Metabolic Implications

“…In addition, MSCs improved liver regeneration by showing proproliferative and antiapoptotic properties, thus preventing disease progress. [15][16][17] These proregenerative characteristics of MSCs might also improve the regenerative capacity of the remaining liver after extensive resection. Here, we tested this hypothesis in a rat model of 90% liver resection.…”