Primary Cilia in Hepatic Biliary Hyperplasia: Implications for Liver Diseases

Abstract

Primary cilia, hair-like projections on the surface of various cell types, play crucial roles in sensing and regulating environmental cues within the liver, particularly among cholangiocytes. These structures detect changes in bile composition, flow, and other biochemical signals, integrating this information to modulate cellular processes. Dysfunction in cholangiocyte cilia-whether due to structural abnormalities or genetic mutations-has been linked to an array of cholangiopathies and ciliopathies. These include conditions such as biliary atresia, cholangiocarcinoma, primary sclerosing cholangitis, and polycystic liver diseases, each with distinct clinical phenotypes influenced by impaired ciliary function. Given the complexity of the ciliary proteome and its role in cellular signaling, including the Hedgehog, Wnt, and TGR5 pathways, ciliary dysfunction disrupts essential signaling cascades, thus driving disease progression. While over 40 gene mutations are associated with ciliopathic features, there may be additional contributors within the expansive ciliary proteome. This study synthesizes current knowledge on cholangiocyte cilia, emphasizing their mechanistic role in liver disease, and highlights emerging therapeutic strategies aimed at restoring ciliary function. In conclusion, ciliotherapies are proposed as a promising approach for addressing cholangiopathies, with the potential to shift the current therapeutic landscape.

Fig. 1

Ciliogenesis. During extracellular ciliogenesis, the cilium emerges directly at the cell membrane. Key proteins, including ARL13B and IFT-A/B (intraflagellar transport proteins), participate in the transport and regulation of components along the cilium. The ciliary membrane covers the axoneme, which extends from the basal body, connecting the cilium to the cell surface. The ciliary pocket, near the base of the cilium, is an incision of the plasma membrane that facilitates membrane trafficking. Ciliogenesis begins when the mother centriole, targeted to become the basal body, links with a small vesicle to form a ciliary vesicle precursor. The early phase is assisted by MYO5A, a motor protein. EHD1 subsequently promotes the growth of the ciliary vesicle, which combines with the basal body. As the cilium begins to develop, so does its associated ciliary sheath. The proteins ARL13B and IFT-A/B are recruited to promote the elongation of the axoneme. The transition zone (TZ), comprising MKS/NPHP proteins, regulates access to the cilium, consequently maintaining appropriate protein composition. As the cilium elongates, it ultimately contacts the plasma membrane, enabling the axoneme to protrude from the cell surface. Insert: Cross-sectional view of the cilium. Primary cilia exhibit a 9 + 0 microtubule structure, while motile cilia feature a 9 + 2 arrangement and possess dynein arms and radial spokes for movement. (Created with BioRender).

Fig. 2

Cholangiocytes express primary cilia. An enlarged cross-section of the liver shows its functional microscopic organization into lobules, where the portal triad (the hepatic artery, portal vein, and bile duct) regulates important liver functions. The primary cilia of cholangiocytes, which line the bile ducts, are sensors for bile flow, osmosis, and chemical signals. The cilia regulate essential signaling pathways like EGFR, FGFR, Wnt, and TGFßR, which impact cell proliferation and survival. Calcium and cAMP signaling are at the core of the multisensory functions of primary cilia and regulate the functions of cholangiocytes. (Created with BioRender).

Fig. 3

Primary cilia sense the extracellular environment. Primary cilia detect external signals via receptors on their surface, leading to the activation or inhibition of distinct signaling pathways. EGFR, epidermal growth factor receptor; LKB1, liver kinase B1; P2YR, purinergic receptors; PC-1, polycystin-1; PC-2, polycystin-2; PDGFRα, platelet-derived growth factor receptor α; PTCH, patched receptor; SMO, smoothened receptor; TGR5, G-protein-coupled bile acid receptor 1; TRPV4, transient receptor potential vanilloid 4. (Created with BioRender).

Fig. 4

Primary cilia and liver diseases. Bile duct abnormalities linked to hepatic biliary hyperplasia are depicted. i) The absence of primary cilia in cholangiocarcinoma results in the unregulated proliferation of bile duct cells and the development of tumoral growth. ii) Malfunctioning cilia in polycystic liver disease leads to bile duct hyperplasia and the development of cysts. iii) Primary biliary cholangitis is characterized primarily by inflammation, oxidative stress, and autophagy in the smaller bile ducts. Cholangiocyte hyperplasia is a secondary, less prominent response to ongoing bile duct injury, but no links to primary cilia defects have been described to date. iv) The clinical presentation of primary sclerosing cholangitis includes the restriction of bile ducts, infiltration of immune cells, and cholangitis; potential links to primary cilia involvement are emerging. v) Biliary atresia is a rare, life-threatening liver disease in infants where the bile ducts become inflamed, blocked, or absent, preventing bile flow from the liver to the intestines and leading to liver damage. (Created with BioRender).