Development of liver microtissues with functional biliary ductular network

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Hafiz E.O.A.; Bulutoglu B.; Mansy S.S.; Chen Y.; Abu-Taleb H.; Soliman S.A.M.; El-Hindawi A.A.F.; Yarmush M.L.; Uygun B.E.

Journal: Biotechnology and Bioengineering

Publisher: John Wiley and Sons Inc

Publication Date: 14 September 2020

Volume / Issue: Volume 118 / Issue 1

Pages: 17–29

ISSN: 63592

DOI: 10.1002/bit.27546

Scopus: View on Scopus

PubMed: 32856740

Document Type: Article

Access: All Open Access; Green Open Access

Authors and Affiliations

Hafiz E.O.A., Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Shriners Hospitals for Children in Boston, Boston, MA, United States, Electron Microscopy Research Department, Theodor Bilharz Research Institute (TBRI), Giza, Egypt; Bulutoglu B., Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Shriners Hospitals for Children in Boston, Boston, MA, United States, Department of Protein Chemistry, Genentech, South San Francisco, CA, United States; Mansy S.S., Electron Microscopy Research Department, Theodor Bilharz Research Institute (TBRI), Giza, Egypt; Chen Y., Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Shriners Hospitals for Children in Boston, Boston, MA, United States; Abu-Taleb H., Immunology and Therapeutic Evaluation Department, TBRI, Giza, Egypt; Soliman S.A.M., Pathology Department, Kasr Al Ainy, Faculty of Medicine, Cairo University, Giza, Egypt; El-Hindawi A.A.F., Pathology Department, Kasr Al Ainy, Faculty of Medicine, Cairo University, Giza, Egypt; Yarmush M.L., Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Shriners Hospitals for Children in Boston, Boston, MA, United States; Uygun B.E., Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Shriners Hospitals for Children in Boston, Boston, MA, United States

Abstract

Liver tissue engineering aims to create transplantable liver grafts that can serve as substitutes for donor's livers. One major challenge in creating a fully functional liver tissue has been to recreate the biliary drainage in an engineered liver construct through integration of bile canaliculi (BC) with the biliary ductular network that would enable the clearance of bile from the hepatocytes to the host duodenum. In this study, we show the formation of such a hepatic microtissue by coculturing rat primary hepatocytes with cholangiocytes and stromal cells. Our results indicate that within the spheroids, hepatocytes maintained viability and function for up to 7 days. Viable hepatocytes became polarized by forming BC with the presence of tight junctions. Morphologically, hepatocytes formed the core of the spheroids, while cholangiocytes resided at the periphery forming a monolayer microcysts and tubular structures extending outward. The spheroids were subsequently cultured in clusters to create a higher order ductular network resembling hepatic lobule. The cholangiocytes formed functional biliary ductular channels in between hepatic spheroids that were able to collect, transport, and secrete bile. Our results constitute the first step to recreate hepatic building blocks with biliary drainage for repopulating the whole liver scaffolds to be used as transplantable liver grafts. © 2020 Wiley Periodicals LLC

Keywords

biliary ductular network; cholangiocytes; hepatocytes; liver tissue engineering; spheroids; Animals; Bile Ducts; Cells, Cultured; Liver; Rats; Spheroids, Cellular; Tissue Engineering; Drainage; Tissue; Biliary drainage; Building blockes; Higher-order; Primary hepatocytes; Stromal cells; Tight junctions; Tubular structures; animal cell; animal tissue; Article; bile canaliculus; bile duct; bile flow; bile secretion; cell function; cell size; cell structure; cell viability; cholangiocyte; coculture; controlled study; liver cell; liver development; liver function; liver lobule; liver microtissue; liver tissue; multicellular spheroid; nonhuman; primary cell culture; rat; stroma cell; tight junction; animal; cell culture; cytology; metabolism

Citation Information

Scopus Citations: 13

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