Regenerative Medicine and the Biliary Tree

Abstract

Despite decades of basic research, biliary diseases remain prevalent, highly morbid, and notoriously difficult to treat. We have, however, dramatically increased our understanding of biliary developmental biology, cholangiocyte pathophysiology, and the endogenous mechanisms of biliary regeneration and repair. All of this complex and rapidly evolving knowledge coincides with an explosion of new technological advances in the area of regenerative medicine. New breakthroughs such as induced pluripotent stem cells and organoid culture are increasingly being applied to the biliary system; it is only a matter of time until new regenerative therapeutics for the cholangiopathies are unveiled. In this review, the authors integrate what is known about biliary development, regeneration, and repair, and link these conceptual advances to the technological breakthroughs that are collectively driving the emergence of a new global field in biliary regenerative medicine.

Figure 1. Spatio-temporal Regulation of Cholangiocyte Development

Schematic representation of key factors involved in biliary development from hepatoblasts. FGF: Fibroblast growth factor, BMP: Bone morphogenetic protein, STM: Septum tranversum mesenchyme, TGFβ: Transforming growth factor beta.

Figure 2. Biliary Development, Regeneration, and Repair

A) Biliary development involving differentiation of hepatoblasts. B) Biliary regeneration involving homeostatic self-replication of cholangiocytes in normal liver or accelerated self-replication following partial hepatectomy. C) Biliary repair involving activation and maturation of biliary precursors.

Figure 3. iPSC-Derived Cholangiocytes and Applications

Schematic depicting patient-derived iPSC that could potentially be expanded as organoids, utilized for disease modelling and drug screening, tested in vivo, and eventually returned to the patient as an individualized therapy.