Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver
10.1007/s13770-020-00274-4
- Author:
Ying-Hsien KAO
1
;
Yu-Chun LIN
;
Po-Huang LEE
;
Chia-Wei LIN
;
Po-Han CHEN
;
Tzong-Shyuan TAI
;
Yo-Chen CHANG
;
Ming-Huei CHOU
;
Chih-Yang CHANG
;
Cheuk-Kwan SUN
Author Information
1. Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung 82445, Taiwan
- Publication Type:O RI G I N A L A R T I C L E
- From:
Tissue Engineering and Regenerative Medicine
2020;17(5):671-682
- CountryRepublic of Korea
- Language:English
-
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.
