Human Wharton's Jelly-derived mesenchymal stem cells prevent acetaminophen-induced liver injury in a mouse model unlike human dermal fibroblasts.

Abstract

The persistence of hepatotoxicity induced by N-acetyl-para-aminophenol (Acetaminophen or Paracetamol, abbreviated as APAP) as the most common cause of acute liver failure in the United States, despite the availability of N-acetylcysteine, illustrates the clinical relevance of additional therapeutic approaches. While human mesenchymal stem cells (MSCs) have shown protection in mouse models of liver injury, the MSCs used are generally not cleared for human use and it is unclear whether these effects are due to xenotransplantation. Here we evaluated GMP manufactured clinical grade human Wharton's Jelly mesenchymal stem cells (WJMSCs), which are currently being investigated in human clinical trials, in a mouse model of APAP hepatotoxicity in comparison to human dermal fibroblasts (HDFs) to address these issues. C57BL6J mice were treated with a moderate APAP overdose (300 mg/kg) and WJMSCs were administered 90 min later. Liver injury was evaluated at 6 and 24 h after APAP. WJMSCs treatment reduced APAP-induced liver injury at both time points unlike HDFs, which showed no protection. APAP-induced JNK activation as well as AIF and Smac release from mitochondria were prevented by WJMSCs treatment without influencing APAP bioactivation. Mechanistically, WJMSCs treatment upregulated expression of Gclc and Gclm to enhance recovery of liver GSH levels to attenuate mitochondrial dysfunction and accelerated recovery of pericentral hepatocytes to re-establish liver zonation and promote liver homeostasis. Notably, preventing GSH resynthesis with buthionine sulfoximine prevented the protective effects of WJMSCs. These data indicate that these GMP-manufactured WJMCs could be a clinically relevant therapeutic approach in the management of APAP hepatotoxicity in humans.

• Authors: David S Umbaugh, Rupal P Soder, Nga T Nguyen, Olamide Adelusi, Dakota R Robarts, Ben Woolbright, Luqi Duan, Sunil Abhyankar, Buddhadeb Dawn, Udayan Apte, Hartmut Jaeschke, Anup Ramachandran
• Journal: Archives of toxicology (Arch Toxicol) Vol. 96 Issue 12 Pg. 3315-3329 (12 2022) ISSN: 1432-0738 [Electronic] Germany
• PMID: 36057886 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Acetaminophen
• Acetylcysteine
• Buthionine Sulfoximine

Topics

• Humans
• Mice
• Animals
• Acetaminophen (metabolism)
• Acetylcysteine (pharmacology)
• Wharton Jelly
• Chemical and Drug Induced Liver Injury (etiology, prevention & control, metabolism)
• Buthionine Sulfoximine (metabolism, pharmacology)
• Chemical and Drug Induced Liver Injury, Chronic
• Liver
• Hepatocytes
• Disease Models, Animal
• Fibroblasts
• Mesenchymal Stem Cells
• Mice, Inbred C57BL