Regenerative Medicine of the Bile Duct: Beyond the Myth

Abstract

Cholangiopathies are rare diseases of the bile duct with high mortality rates. The current treatment for cholangiopathies is liver transplantation, but there are significant obstacles including a shortage of donors and a high risk of complications. Currently, there is only one available medicine on the market targeting cholangiopathies, and the results have been inadequate in clinical therapy. To overcome these obstacles, many researchers have used human induced pluripotent stem cells (hPSC) as a source for cholangiocyte-like cell generation and have incorporated advances in bioprinting to create artificial bile ducts for implantation and transplantation. This has allowed the field to move dramatically forward in studies of biliary regenerative medicine. In this review, the authors provide an overview of cholangiocytes, the organogenesis of the bile duct, cholangiopathies, and the current treatment and advances that have been made that are opening new doors to the study of cholangiopathies.

Tissue-Engineered Bile Ducts for Disease Modeling and Therapy

“…To study cholangiopathies, testing of new drugs and the (clinical) application of tissue engineering approaches, in vitro long-term maintenance of cholangiocytes and generation of biliary tissue is of utmost importance. 11,12 Thereto, the anatomical and functional features of the tissue should be replicated in vitro, which is currently hindered by a lack of adequate in vitro culture systems and suitable scaffolds. 12 The possibility to induce differentiation of cholangiocytes from pluripotent stem cells (PSCs) has resulted in novel opportunities to establish reliable in vitro culture systems of cholangiocytes.…”

“…11,12 Thereto, the anatomical and functional features of the tissue should be replicated in vitro, which is currently hindered by a lack of adequate in vitro culture systems and suitable scaffolds. 12 The possibility to induce differentiation of cholangiocytes from pluripotent stem cells (PSCs) has resulted in novel opportunities to establish reliable in vitro culture systems of cholangiocytes. [13][14][15] Cholangiocytes and cholangiocytebased organoids derived from induced pluripotent stem cells (iPSCs) are advancements in the field of liver cell culture and the emerging field of tissue engineering, specifically bile duct engineering, offering a variety of choices regarding cell source and desired differentiated cell type.…”

Self-Organogenesis from 2D Micropatterns to 3D Biomimetic Biliary Trees

“…Even though the biliary system plays a critical role in food digestion and liver detoxification [1], bioengineering of a functional biliary tree has not yet been successful. Several approaches have been described in an effort to bioengineer bile ducts: from spontaneous self-organization of rodent or human cholangiocytes, cholangiocytes from bile, and cholangiocyte-like cells differentiated from liver progenitor cells into functional spheroids and tube fragments in natural hydrogels or decellularized extracellular matrix (dECM) either as mono-cultures or co-cultures with other liver cells [2][3][4][5][6]; to the construction of biliary tubes from populated tubular constructs, or bioprinting in hepatic dECM and the development of functional biliary tube fragments in a microfluidic chip [7][8][9]. Moreover, the effects of the media flow on the hepatocyte phenotype and functions were investigated on a 3D hepatobiliary model [10].…”

Bile duct reconstruction using scaffold-free tubular constructs created by Bio-3D printer

“…To overcome these biliary complications, many types of artificial bile ducts have been evaluated as potential substitutes for native bile ducts [ 10 , [13] , [14] , [15] , [16] , [17] ]; however, a range of problems, including immune reactions, the safety of degradation products from the artificial bile ducts, disease or infection transmission, and acute allergic responses, have hindered their clinical application [ 18 ].…”