Human vascularized bile duct-on-a chip: a multi-cellular micro-physiological system for studying cholestatic liver disease

被引:12
|
作者
Du, Yu [1 ,2 ,3 ,4 ]
de Jong, Iris E. M. [1 ,4 ]
Gupta, Kapish [1 ,4 ]
Waisbourd-Zinman, Orit [5 ,6 ]
Har-Zahav, Adi [5 ,6 ]
Soroka, Carol J. [7 ]
Boyer, James L. [7 ]
Llewellyn, Jessica [1 ,4 ]
Liu, Chengyang [8 ]
Naji, Ali [8 ]
Polacheck, William J. [9 ,10 ]
Wells, Rebecca G. [1 ,4 ,11 ,12 ]
机构
[1] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA
[2] Chinese Acad Sci, Key Lab Micrograv, Ctr Biomech & Bioengn, Natl Micrograv Lab, Beijing 100190, Peoples R China
[3] Chinese Acad Sci, Inst Mech, Beijing Key Lab Engn Construct & Mechanobiol, Beijing 100190, Peoples R China
[4] Univ Penn, NSF Sci & Technol Ctr Engn MechanoBiol, Philadelphia, PA 19104 USA
[5] Schneider Childrens Med Ctr Israel, Inst Gastroenterol Nutr & Liver Dis, Petah Tiqwa, Israel
[6] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
[7] Yale Univ, Sect Digest Dis& Liver Ctr, Dept Internal Med, Sch Med, New Haven, CT USA
[8] Univ Penn, Dept Surg, Philadelphia, PA USA
[9] Univ North Carolinaat Chapel Hill, Joint Dept Biomed Engn, Chapel Hill, NC USA
[10] North Carolina State Univ, Chapel Hill, NC USA
[11] Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA
[12] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA
关键词
microfluidic device; cholangiopathy; tissue engineering; organ-on-a-chip; primary sclerosing cholangitis; PRIMARY SCLEROSING CHOLANGITIS; ORGANOIDS; CELLS; DIFFERENTIATION; CULTURE;
D O I
10.1088/1758-5090/ad0261
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Exploring the pathogenesis of and developing therapies for cholestatic liver diseases such as primary sclerosing cholangitis (PSC) remains challenging, partly due to a paucity of in vitro models that capture the complex environments contributing to disease progression and partly due to difficulty in obtaining cholangiocytes. Here we report the development of a human vascularized bile duct-on-a-chip (VBDOC) that uses cholangiocyte organoids derived from normal bile duct tissue and human vascular endothelial cells to model bile ducts and blood vessels structurally and functionally in three dimensions. Cholangiocytes in the duct polarized, formed mature tight junctions and had permeability properties comparable to those measured in ex vivo systems. The flow of blood and bile was modeled by perfusion of the cell-lined channels, and cholangiocytes and endothelial cells displayed differential responses to flow. We also showed that the device can be constructed with biliary organoids from cells isolated from both bile duct tissue and the bile of PSC patients. Cholangiocytes in the duct became more inflammatory under the stimulation of IL-17A, which induced peripheral blood mononuclear cells and differentiated Th17 cells to transmigrate across the vascular channel. In sum, this human VBDOC recapitulated the vascular-biliary interface structurally and functionally and represents a novel multicellular platform to study inflammatory and fibrotic cholestatic liver diseases.
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页数:13
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