Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver

Abstract

Background:

This study investigated whether xenotransplantation of human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism.

Methods:

Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies.

Results:

WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-β1-stimulation in Smad2 phosphorylation and RhoA upregulation.

Conclusion:

These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.

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Acknowledgements

The authors would like to dedicate this article to late Professor Daniel Tzu-Bi Shih in memory of his earnestness and generosity in disseminating his knowledge and sharing his expertise with his fellow researchers. This study was supported by the Grants from E-Da Hospital (EDAHP102043 to CYC; NCKUEDA10513 to YHK; EDAHT107047 to CKS). YHK, CYC and CKS conceived the study, supervised the experiments and finalized the draft. YHK and YCL wrote the paper. YCL, CWL and PHC performed the experiments. PHL, TST, YCC, and MHC contributed to analysis tools and analyzed the data. All authors have reviewed the manuscript and approved submission.

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YHK, CYC and CKS conceived the study, supervised the experiments and finalized the draft. YHK and YCL wrote the paper. YCL, CWL and PHC performed the experiments. PHL, TST, YCC, and MHC contributed to analysis tools and analyzed the data. All authors have reviewed the manuscript and approved submission.

Corresponding authors

Correspondence to Chih-Yang Chang or Cheuk-Kwan Sun.

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The authors declare that they have no conflict of interest.

Ethical statement

The study protocol was approved by the institutional reviewing board of E-Da Hospital (IRB No. EMRP26100N). Informed consent was confirmed by the IRB. The animal studies were performed after receiving approval of the Institutional Animal Care and Use Committee at E-Da Hospital (IACUC Approval No. IACUC-101017).

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Kao, Y., Lin, Y., Lee, P. et al. Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver. Tissue Eng Regen Med (2020). https://doi.org/10.1007/s13770-020-00274-4

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Keywords

  • Human umbilical cord
  • Hepatotoxin
  • Liver fibrosis
  • Plasma fibronectin
  • Wharton’s jelly tissue