Pedro M Baptista1,2,3,4, Emma C Moran1, Dipen Vyas1, Maria H Ribeiro5, Anthony Atala1, Jessica L Sparks6, Shay Soker1. 1. 1 Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences , Winston-Salem, North Carolina. 2. 2 University of Zaragoza , Zaragoza, Spain . 3. 3 IIS Aragón , CIBERehd, Zaragoza, Spain . 4. 4 Aragon Health Sciences Institute (IACS) , Zaragoza, Spain . 5. 5 Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), University of Lisbon , Lisbon, Portugal . 6. 6 Department of Chemical, Paper and Biomedical Engineering, Miami University , Oxford, Ohio.
Abstract
OBJECTIVE: Modeling of human liver development, especially cellular organization and the mechanisms underlying it, is fundamental for studying liver organogenesis and congenital diseases, yet there are no reliable models that mimic these processes ex vivo. DESIGN: Using an organ engineering approach and relevant cell lines, we designed a perfusion system that delivers discrete mechanical forces inside an acellular liver extracellular matrix scaffold to study the effects of mechanical stimulation in hepatic tissue organization. RESULTS: We observed a fluid flow rate-dependent response in cell distribution within the liver scaffold. Next, we determined the role of nitric oxide (NO) as a mediator of fluid flow effects on endothelial cells. We observed impairment of both neovascularization and liver tissue organization in the presence of selective inhibition of endothelial NO synthase. Similar results were observed in bioengineered livers grown under static conditions. CONCLUSION: Overall, we were able to unveil the potential central role of discrete mechanical stimulation through the NO pathway in the revascularization and cellular organization of a bioengineered liver. Last, we propose that this organ bioengineering platform can contribute significantly to the identification of physiological mechanisms of liver organogenesis and regeneration and improve our ability to bioengineer livers for transplantation.
OBJECTIVE: Modeling of human liver development, especially cellular organization and the mechanisms underlying it, is fundamental for studying liver organogenesis and congenital diseases, yet there are no reliable models that mimic these processes ex vivo. DESIGN: Using an organ engineering approach and relevant cell lines, we designed a perfusion system that delivers discrete mechanical forces inside an acellular liver extracellular matrix scaffold to study the effects of mechanical stimulation in hepatic tissue organization. RESULTS: We observed a fluid flow rate-dependent response in cell distribution within the liver scaffold. Next, we determined the role of nitric oxide (NO) as a mediator of fluid flow effects on endothelial cells. We observed impairment of both neovascularization and liver tissue organization in the presence of selective inhibition of endothelial NO synthase. Similar results were observed in bioengineered livers grown under static conditions. CONCLUSION: Overall, we were able to unveil the potential central role of discrete mechanical stimulation through the NO pathway in the revascularization and cellular organization of a bioengineered liver. Last, we propose that this organ bioengineering platform can contribute significantly to the identification of physiological mechanisms of liver organogenesis and regeneration and improve our ability to bioengineer livers for transplantation.
Authors: Meritxell Huch; Helmuth Gehart; Ruben van Boxtel; Karien Hamer; Francis Blokzijl; Monique M A Verstegen; Ewa Ellis; Martien van Wenum; Sabine A Fuchs; Joep de Ligt; Marc van de Wetering; Nobuo Sasaki; Susanne J Boers; Hans Kemperman; Jeroen de Jonge; Jan N M Ijzermans; Edward E S Nieuwenhuis; Ruurdtje Hoekstra; Stephen Strom; Robert R G Vries; Luc J W van der Laan; Edwin Cuppen; Hans Clevers Journal: Cell Date: 2014-12-18 Impact factor: 41.582
Authors: Dipen Vyas; Pedro M Baptista; Matthew Brovold; Emma Moran; Brandon Gaston; Chris Booth; Michael Samuel; Anthony Atala; Shay Soker Journal: Hepatology Date: 2018-01-02 Impact factor: 17.425
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Authors: Kewei Li; Mohammad Tharwat; Ellen L Larson; Philipp Felgendreff; Seyed M Hosseiniasl; Anan Abu Rmilah; Khaled Safwat; Jeffrey J Ross; Scott L Nyberg Journal: Front Bioeng Biotechnol Date: 2022-03-10