Tissue Eng Regen Med.  2020 Oct;17(5):671-682. 10.1007/s13770-020-00274-4.

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

• Kao YH
• Lin YC
• Lee PH
• Lin CW
• Chen PH
• Tai TS
• Chang YC
• Chou MH
• Chang CY
• Sun CK

• KMID: 2507320
• DOI: http://doi.org/10.1007/s13770-020-00274-4

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-b1-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.

Keyword

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