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 Sun8,9. 1. Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan. 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. 5. Graduate Institute of Clinical Medical Sciences, Chang Gung University College Medicine, Kaohsiung, Taiwan. 6. Center for General Education, Cheng-Shiu University, Kaohsiung, Taiwan. 7. Department of Gynecology and Obstetrics, E-Da Hospital, I-Shou University, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan. kentyan.chang@msa.hinet.net. 8. Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan. lawrence.c.k.sun@gmail.com. 9. The School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan. lawrence.c.k.sun@gmail.com.
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.
BACKGROUND: This study investigated whether xenotransplantation of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouseliver fibrosis and the underlying molecular mechanism. METHODS: Recipient NOD/SCIDmice 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.
Authors: María José Sáez-Lara; Cecilia Frecha; Francisco Martín; Francisco Abadía; Miguel Toscano; Angel Gil; Luis Fontana Journal: Xenotransplantation Date: 2006-11 Impact factor: 3.907
Authors: Marcela M De Luna-Saldivar; Iván A Marino-Martinez; Moisés A Franco-Molina; Lydia G Rivera-Morales; Gabriela Alarcón-Galván; Paula Cordero-Pérez; Augusto Rojas-Martínez; Cristina Rodríguez-Padilla; Linda E Muñoz-Espinosa Journal: Ann Hepatol Date: 2019-05-15 Impact factor: 2.400