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Amelioration of Acetaminophen-Induced Liver Injury Via Delta Opioid Receptor–Activated Human Mesenchymal Stem Cells—an In Vivo Approach

  • Madhubanti Mullick
  • Srijita Banerjee
  • Dwaipayan SenEmail author
Article
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Abstract

Background

Liver injury poses to be a prevalent and persistent problem at a global scale and liver transplantation using umbilical cord blood–borne human mesenchymal stem cells (hMSCs) being the frequent respite to overcome it. Although there has been a plethora of advancements in liver transplantation studies, failures of a successful transplant remain difficult to evade, majorly due to lack of hMSC survivability at the injured site. Hence, in this study, the effect of delta opioid receptor (DOR)–activated hMSCs, reported to have shown a pronounced increase in hMSC survivability in vitro under different stress conditions, have been illustrated on an acute liver injury model of mice.

Methods

Acetaminophen, a commonly used paracetamol for induction of liver injury was administered intraperitoneally at a dosage of 500 mg/kg to the treatment groups of mice. The control groups included without treatment phosphate buffer saline (PBS) injected. For the transplantation of hMSCs, tail vein injection route of administration was followed at a dose of 5 × 105 cells/ animal. After 48 h, the liver tissues and blood samples were collected for determination of the ALT-AST activity and the alterations in the levels of inflammatory cytokines. Alongside, liver tissues were fixed using 10% formalin and observed for portal and lobular inflammation.

Results

The transplantation of hMSCs prevented the increase in the levels of serum alanine transaminase and aspartate transaminase, respectively, in comparison with the acetaminophen-treated groups. There was an additional repression observed in their levels upon transplantation with DOR-activated hMSCs. Analysis of the inflammatory cytokines post-induction and transplantation of hMSCs and DOR-activated hMSCs revealed a prominent mitigation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α by over ~ 4-folds and a significant upregulation of anti-inflammatory cytokine IL-10 by about ~ 4-folds when compared to the acetaminophen-treated. Histological evidences of the liver tissue samples also followed a similar trend wherein maximum necrotic tissues were observed in the groups treated with acetaminophen. The groups transplanted with hMSCs showed potential recuperation from necrosis and inflammation, which were further curbed down in groups transplanted with DOR-activated hMSCs.

Conclusion

This study corroborates the potential benefits of transplanting DOR-activated hMSCs in a liver injury mice model and implies that recuperation of the mice groups with DOR-administered hMSCs was majorly due to the amelioration in the inflammatory cytokines, along with subdued levels of ALT-AST enzymes. Therefore, DOR activation on hMSCs could prove to be a successful prospective therapeutic for a repertoire of such liver failure models.

Keywords

hMSCs DOR-activated hMSCs Liver injury Acetaminophen Inflammation 

Notes

Acknowledgements

The authors are grateful to Ms. Moghal Erfath Thanjeem Begum and Ms. Pearlin Hameed for their liberal support in handling and treatment procedures of the mice.

Authors’ Contributions

MM has carried out experiments, analyzed data, and wrote the paper. SB has carried out experiments. DS conceptualized, wrote the paper, and analyzed the data.

Source of Funding

This study was funded by “SEED” grant from VIT, Vellore awarded to DS.

Compliance with Ethical Standards

All animal experiments were reviewed and approved by the Institutional animal ethics committee of VIT, Vellore, India.

Consent for Publication

All the authors have read the manuscript and agreed to the publication.

Competing Interests

The authors declare that there are no conflicts of interest.

References

  1. 1.
    Kim HJ, Park J-S. Usage of human mesenchymal stem cells in cell-based therapy: advantages and disadvantages. Dev Reprod. 2017;21:1–10.CrossRefGoogle Scholar
  2. 2.
    Singh A, Singh A, Sen D. Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015). Stem Cell Res Ther. 2016;7:82.CrossRefGoogle Scholar
  3. 3.
    Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng. 2010;12:87–117.CrossRefGoogle Scholar
  4. 4.
    Faiella W, Atoui R. Immunotolerant properties of mesenchymal stem cells: updated review. Stem Cells Int. 2016;2016:1–7.CrossRefGoogle Scholar
  5. 5.
    Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428:664–8.CrossRefGoogle Scholar
  6. 6.
    Kaminski N, Phinney DG, Baddoo M, Gambelli F, McBride C, Ortiz LA, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100(14):8407–11.CrossRefGoogle Scholar
  7. 7.
    Yannarelli G, Tsoporis JN, Desjardins JF, Wang XH, Pourdjabbar A, Viswanathan S, et al. Donor mesenchymal stromal cells (MSCs) undergo variable cardiac reprogramming in vivo and predominantly co-express cardiac and stromal determinants after experimental acute myocardial infarction. Stem Cell Rev Rep. 2014;10:304–15.CrossRefGoogle Scholar
  8. 8.
    Chapel A, Bertho JM, Bensidhoum M, Fouillard L, Young RG, Frick J, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5:1028–38.CrossRefGoogle Scholar
  9. 9.
    Yadav N, Kanjirakkuzhiyil S, Kumar S, Jain M, Halder A, Saxena R, et al. The therapeutic effect of bone marrow-derived liver cells in the phenotypic correction of murine hemophilia a. Blood. 2009;114:4552–61.CrossRefGoogle Scholar
  10. 10.
    Mullick M, Venkatesh K, Sen D. D-alanine 2, leucine 5 enkephaline (DADLE)-mediated DOR activation augments human hUCB-BFs viability subjected to oxidative stress via attenuation of the UPR. Stem Cell Res. 2017;22:20–8.CrossRefGoogle Scholar
  11. 11.
    Reddy LVK, Sen D. DADLE enhances viability and anti-inflammatory effect of human MSCs subjected to ‘serum free’ apoptotic condition in part via the DOR/PI3K/AKT pathway. Life Sci. 2017;191:195–204.CrossRefGoogle Scholar
  12. 12.
    Mullick M, Sen D. The delta opioid peptide DADLE represses hypoxia-reperfusion mimicked stress mediated apoptotic cell death in human mesenchymal stem cells in part by downregulating the unfolded protein response and ROS along with enhanced anti-inflammatory effect. Stem Cell Rev Rep. 2018;14:558–73.CrossRefGoogle Scholar
  13. 13.
    Zheng S, Yang J, Yang J, Tang Y, Shao Q, Guo L, et al. Transplantation of umbilical cord mesenchymal stem cells via different routes in rats with acute liver failure. Int J Clin Exp Pathol. 2015;8(12):15854–62.Google Scholar
  14. 14.
    Williams R, Schalm SW, O’Grady JG. Acute liver failure: redefining the syndromes. Lancet. 1993;342:273–5.CrossRefGoogle Scholar
  15. 15.
    Hay JE. Acute liver failure. Curr Treat Options Gastroenterol. 2004;7:459–68.CrossRefGoogle Scholar
  16. 16.
    Jaeschke H. Mechanisms of sterile inflammation in acetaminophen hepatotoxicity. Cell Mol Immunol. 2018;15:74–5.CrossRefGoogle Scholar
  17. 17.
    Lawson J, Farhood A, Hopper R. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci. 2000;54:509–16.CrossRefGoogle Scholar
  18. 18.
    Shen W, Kamendulis LM, Ray SD, Corcoran GB. Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: correlation of nuclear Ca2+ accumulation and early DNA fragmentation with cell death. Toxicol Appl Pharmacol. 1991;111:242–54.CrossRefGoogle Scholar
  19. 19.
    Jaeschke H, Bajt ML. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci. 2006;89:31–41.CrossRefGoogle Scholar
  20. 20.
    Gurule MW, Yorkin RD, Kamendulis LM, Ray SD, Corcoran GB. Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J. 2018.Google Scholar
  21. 21.
    Jan YH, Heck DE, Dragomir AC, Gardner CR, Laskin DL, Laskin JD. Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Chem Res Toxicol. 2014;27:882–94.CrossRefGoogle Scholar
  22. 22.
    Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin N Am. 2008;92:761–94.CrossRefGoogle Scholar
  23. 23.
    Gabriel N, Samuel R, Jayandharan GR. Targeted delivery of AAV-transduced mesenchymal stromal cells to hepatic tissue for ex vivo gene therapy. J Tissue Eng Regen Med. 2017;11:1354–64.CrossRefGoogle Scholar
  24. 24.
    Begum MET, Sen D. DOR agonist (SNC-80) exhibits anti-parkinsonian effect via downregulating UPR/oxidative stress signals and inflammatory response in vivo. Neurosci Lett. 2018;678:29–36.CrossRefGoogle Scholar
  25. 25.
    Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009;4:206–16.CrossRefGoogle Scholar
  26. 26.
    Park M, Kim YH, Woo SY, Lee HJ, Yu Y, Kim HS, et al. Tonsil-derived mesenchymal stem cells ameliorate CCl4-induced liver fibrosis in mice via autophagy activation. Sci Rep. 2015;5:8616.CrossRefGoogle Scholar
  27. 27.
    Lawson JA. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci. 2002;54(2):509–16.CrossRefGoogle Scholar
  28. 28.
    Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973;187(1):185–94.Google Scholar

Copyright information

© The Regenerative Engineering Society 2019

Authors and Affiliations

  1. 1.Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT)Vellore Institute of Technology (VIT)VelloreIndia
  2. 2.School of Biosciences and TechnologyVellore Institute of Technology (VIT)VelloreIndia

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