Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver
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Online ISSN 2212-5469
ORIGINAL ARTICLE
Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver Ying-Hsien Kao1 • Yu-Chun Lin2 • Po-Huang Lee2,3 • Chia-Wei Lin4 • Po-Han Chen1 • Tzong-Shyuan Tai1 • Yo-Chen Chang4 • Ming-Huei Chou5,6 Chih-Yang Chang7 • Cheuk-Kwan Sun1,8
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Received: 9 April 2020 / Revised: 13 May 2020 / Accepted: 14 May 2020 Ó The Korean Tissue Engineering and Regenerative Medicine Society 2020
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. Keywords Human umbilical cord Hepatotoxin Liver fibrosis Plasma fibronectin Wharton’s jelly tissue
Ying-Hsien Kao and Yu-Chun Lin have contributed equally to this work.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13770-020-00274-4) contains supplementary material, which is available to authorized users. & Chih-Yang Chang [email protected]
2
Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
3
Committee for Integration and Promotion of Advanced Medicine and Biotechnology, E-Da Healthcare Group, Kaohsiung, Taiwan
4
Department of Ophthalmology, Kaohsiung Medical University, Kaohsiung, Taiwan
& Cheuk-Kwan Sun lawrence.c.k.sun@g
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