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

  • Organ Toxicity and Mechanisms
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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.

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Acknowledgements

This work was funded in part by a pilot grant from the Midwest Stem Cell Therapy Center, a grant from the Midwest Biomedical Accelerator Consortium (MBArC), an NIH Research Evaluation and Commercialization Hub (REACH), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01 DK102142 and DK125465, and National Institute of General Medicine (NIGMS) funded Liver Disease COBRE grants P20 GM103549 and P30 GM118247.

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  1. Buddhadeb Dawn

    Present address: Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, USA

Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA

    David S. Umbaugh, Nga T. Nguyen, Olamide Adelusi, Dakota R. Robarts, Ben Woolbright, Luqi Duan, Udayan Apte, Hartmut Jaeschke & Anup Ramachandran

  2. Midwest Stem Cell Therapy Center, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1075, Kansas City, KS, 66160, USA

    Rupal P. Soder, Sunil Abhyankar & Buddhadeb Dawn

  3. Blood and Marrow Transplant Program, Division of Hematologic Malignancies and Cellular Therapeutics Center, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA

    Sunil Abhyankar

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  1. David S. Umbaugh
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Umbaugh, D.S., Soder, R.P., Nguyen, N.T. et al. Human Wharton's Jelly-derived mesenchymal stem cells prevent acetaminophen-induced liver injury in a mouse model unlike human dermal fibroblasts. Arch Toxicol 96, 3315–3329 (2022). https://doi.org/10.1007/s00204-022-03372-5

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