Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis

Ludovica Ceci; Eugenio Gaudio; Lindsey Kennedy

doi:10.1016/j.jcmgh.2024.01.005

. 2024 Jan 10;17(4):553–565. doi: 10.1016/j.jcmgh.2024.01.005

Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis

Ludovica Ceci ¹, Eugenio Gaudio ¹, Lindsey Kennedy ^2,^3,^∗

PMCID: PMC10883986 PMID: 38216052

Abstract

Biliary fibrosis is seen in cholangiopathies, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In PBC and PSC, biliary fibrosis is associated with worse outcomes and histologic scores. Within the liver, both hepatic stellate cells (HSCs) and portal fibroblasts (PFs) contribute to biliary fibrosis, but their roles can differ. PFs reside near the bile ducts and may be the first responders to biliary damage, whereas HSCs may be recruited later and initiate bridging fibrosis. Indeed, different models of biliary fibrosis can activate PFs and HSCs to varying degrees. The portal niche can be composed of cholangiocytes, HSCs, PFs, endothelial cells, and various immune cells, and interactions between these cell types drive biliary fibrosis. In this review, we discuss the mechanisms of biliary fibrosis and the roles of PFs and HSCs in this process. We will also evaluate cellular interactions and mechanisms that contribute to biliary fibrosis in different models and highlight future perspectives and potential therapeutics.

Keywords: biliary fibrosis, portal fibroblasts, hepatic stellate cells, ductular reaction, bile acids, angiogenesis, immune cells

Summary.

This comprehensive review highlights important research on biliary fibrosis. We discuss hepatic stellate cells and portal fibroblasts and outline the mechanisms and cellular niches influencing biliary fibrosis in different mouse models.

Cholangiopathies target the bile ducts, leading to fibroinflammatory responses that initiate biliary fibrosis and eventually bridging fibrosis and cirrhosis.¹ Cholangiopathies are diagnosed in pediatric and adult patients, and the 6 most common cholangiopathies include primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cystic fibrosis–associated liver disease, polycystic liver disease, biliary atresia, and cholangiocarcinoma (CCA).¹ PBC and PSC are the most common cholangiopathies, with prevalence reported as 4 in 100,000 and 35 in 100,00, respectively²^,³; thus, these diseases will be the focus of this review.

During PBC and PSC, cholangiocytes undergo proliferative, senescent, apoptotic, and/or transdifferentiating events, which modulate the microenvironment through the secretion of growth factors, cholangiokines, senescent-associated secretory factors (SASPs), etc. Ductular reaction (DR) is the presence of atypical bile ducts that lack an apparent lumen, and DR may arise from cholangiocytes, hepatocytes, or hepatic progenitor cells (HPCs).⁴ It was proposed that senescent cholangiocytes remain at the bile duct and contribute to initial and sustained peribiliary fibrosis via activation of portal fibroblasts (PFs). Contrarily, reactive cholangiocytes undergo proliferation and recruit and activate hepatic stellate cells (HSCs), leading to bridging fibrosis.⁵ Cholangiocyte response to injury is multifaceted, and divergent fates differentially modulate fibrosis.

PBC and PSC injury follows similar steps: (1) persistent biliary damage leads to cholestasis, (2) bile acid (BA) buildup causes hepatocellular damage, (3) consequent inflammation and immune cell infiltration occur, and (4) the complex of biliary and hepatocellular damage and inflammation invoke fibrosis.⁶ However, there is nuance in fibrogenesis between PBC and PSC. In both PBC and PSC, biliary fibrosis starts from the portal tract and progresses with fibrotic septa formation leading to portal-portal pattern fibrosis. At later stages, fibrosis extends to the lobular area and continues into cirrhosis.⁷^,⁸ Furthermore, in PBC, the bile ducts are infiltrated by immune/inflammatory cells that damage the portal tract structure and expand the peribiliary stroma. In PSC, patients are characterized by peribiliary inflammation, concentric fibrosis (onion-like structure) and atrophy, and/or disappearance of small bile ducts. Consequently, in both PSC and PBC, the continuous destruction of intrahepatic bile ducts promotes cholestasis.⁶

Fibrosis stage predicts survival in PBC patients independent of biochemical response.⁹ Similarly, fibrosis-related scores predict poorer outcomes for PSC patients.¹⁰ In PBC and PSC, biliary fibrosis is a shared pathway, an important prognostic factor, and precedes bridging fibrosis. Obviously, biliary fibrosis is an important pathologic process in PBC and PSC. In this review we will discuss mechanisms and cellular interactions regulating biliary fibrosis.

Hepatic Stellate Cells and Portal Fibroblasts: A Tale of Two Cells

HSCs and PFs are the main hepatic mesenchymal cells that synthesize extracellular matrix (ECM).¹¹ Previous research hypothesized that fibrocytes and hepatocytes or cholangiocytes undergoing epithelial to mesenchymal transition (EMT) may contribute to fibrosis; however, in fibrotic livers fibrocytes are only 3%–6% of the collagen type I expressing cells,¹² and neither hepatocytes nor cholangiocytes undergo EMT or contribute to ECM deposition.¹³^,¹⁴ HSCs and PFs comprise >95% of collagen expressing cells in fibrosis models.⁷ Indeed, both PFs and HSCs are involved in collagen deposition around injured bile ducts.¹⁵

During normal states, HSCs and PFs are quiescent and may be transiently activated after acute exposure to pathogens or toxins to maintain homeostasis¹⁶; however, during PBC and PSC, myofibroblast activation is chronic and persistent.¹⁷ HSCs reside in the space of Disse and during quiescence express a neural phenotype; however, injury such as carbon tetrachloride (CCl₄) treatment causes HSCs to release their vitamin A stores, synthesize and secrete collagen type I, proliferate, and obtain a myofibroblast phenotype.¹⁵^,¹⁸^,¹⁹ PFs reside near the portal vein,²⁰ and in the biliary fibrosis model of bile duct ligation (BDL), activated PFs proliferate, take on a myofibroblast phenotype, and secrete collagen type I, collagen type IV, and procollagen III.²¹^,²² Similarities and differences in morphology, features, and characteristics of PFs and HSCs during quiescence and activation are summarized in Table 1. One study suggests that early ECM deposition in biliary fibrosis is due to PF activation after 48 hours of BDL, with HSC contribution after 72 hours of BDL.²² Others have confirmed that PFs are primarily activated in BDL, with partial contribution to HSCs.²³ In addition, portal mesenchymal cells (PMCs) in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding model of biliary fibrosis display PF signatures, are highly proliferative, and contribute to ECM remodeling. Interestingly, HSC-derived myofibroblasts were non-proliferative but still increased Col1a1 expression in vitro, suggesting that PF-derived PMCs initiate fibrotic septa formation and later recruit HSCs.²⁴ BDL surgery and DDC feeding induced PMC proliferation and up-regulation of fibrotic genes that were not seen in HSCs,²⁵ suggesting that these cells are PFs. In Mdr2^-/- mice, activated PFs accounted for 25%, 51%, and 54% of myofibroblasts at 4, 8, and 16 weeks of age, respectively, with the other percentage composed of HSCs,²⁶ signifying that both cell types contribute to biliary fibrosis in Mdr2^-/- mice. Although newer studies identify the importance of PFs in biliary fibrosis, many studies have revolved around HSCs. We will further discuss mechanisms and cellular interactions identified in models of biliary fibrosis that affect PFs and HSCs.

Table 1.

List of PF and HSC Features in Quiescence and Activation

Localization in liver	PFs	HSCs
Localization in liver	Portal vein	Space of Disse
Morphology
Quiescent state	• Flat • Spindle-shaped cells • Dark, oval nucleus • Actively secrete ECM	• Stellate-like shape • Reduced cellular body volume • Spindle-shaped • Voluminous oval or elongated nucleus ○ Often compressed by vitamin A and/or retinoid containing lipid drops placed in the perinuclear cytoplasm • Dilated, rough endoplasmic reticulum • Low number of mitochondria and lysosomes
Activated state	• Spindle-shaped cells • Smooth muscle-like features: ○ Contractile apparatus ○ Prominent rough endoplasmic reticulum ○ Golgi apparatus producing collagen ○ Peripheral myofilaments ○ Fibronexus (no lamina) ○ Gap junctions	• Loss of retinoid/vitamin A lipid droplets • Flat-stellate shape • Expression of contractile fibers (myofibroblast differentiation – contractility) in cytoplasm • Matured rough endoplasmic reticulum associated with a well-formed Golgi apparatus
Functions
Quiescent state	• Maintain integrity of the biliary tree and portal tract	• Balanced ECM turnover • Low proliferation • Storage of vitamin A and retinoids
Activated state	• Proliferative • Contribute to collagen type I deposition • Regulate cholangiocyte proliferation • Maintain cholangiocyte polarity • Support angiogenesis	• Fibrogenesis • ECM synthesis and degradation • Increased cell proliferation • Contractility • Secretion of cytokines, chemokines, and immunomodulatory signals • Acts as antigen-presenting cells • Role in liver development and regeneration (hepatocyte proliferation) • Support angiogenesis and LSEC capillarization
Markers
Quiescent state	• Thy-1 • Fibulin-2 • Elastin • Gremlin-1 • ENTPD2 • IL-6	• Vitamin A • Retinoid • Desmin
Activated state	• Thy-1 • Mesothelin • Fibulin-2 • Elastin • Gremlin-1 • Asporin • IL-6 • Collagen 15A1 • Mucin 16 • ENTPD2 • Endoglin • CD73 • CD143 • ACTA2	• Glial fibrillary acidic protein • Neurotrophin receptor p75 • Synemin • Lecithin:retinol acyltransferase • ACTA2 • Reelin • Endoglin • CD73 • CD143
Injury response	• Primary responders of cholangiocyte damage	• Primary responders of hepatocyte damage
ECM synthesis	• Elastic fibers (elastin core surrounded by fibrillin-rich microfibrils) • Collagen XV	• Collagen I and III • Fibronectin • Thrombospondin-1 • Proteoglycans

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ACTA2, alpha smooth muscle actin; CD, cluster of differentiation; ENTPD2, ectonucleotidase 2; LSEC, lymphatic sinusoidal endothelial cell; Thy-1, thymocyte differentiation antigen-1.

Ductular Reaction: A Catch-22

DR correlates with fibrosis stage in PBC, and higher DR inversely correlates with ursodeoxycholic acid (UDCA) response in PBC.²⁷ In PSC, DR is associated with higher expression of ECM-related genes, including fibronectin-1 (FN-1), laminin subunit gamma-2, and collagens.²⁸ After BDL for 24 hours, DR and portal ECM deposition occur and precede myofibroblast presence that appeared 48 hours after BDL,²¹ indicating that DR prompts myofibroblast activation. In turn, prolyl-4-hydroxylase, an enzyme that synthesizes collagen, promotes DR and biliary fibrosis in DDC-fed mice.²⁹ Cytokeratin-19 (CK-19) is responsible for cell structure and in the liver is a bona fide cholangiocyte marker. Loss of CK-19 reduced DR and biliary fibrosis in DDC-fed mice,³⁰ indicating cholangiocyte involvement in biliary fibrosis. Cholangiocytes have enhanced transforming growth factor (TGF)-β, which induced transcription of FN-1, and blocking this transcriptional regulation in cholangiocytes blunted biliary fibrosis in Mdr2^-/- mice.³¹^,³² Similarly, blocking hepatic TGF-β2 decreased biliary fibrosis in Mdr2^-/- mice.³³ Other studies have found that TgfB2-directed antisense oligonucleotides reduced parenchymal liver fibrosis in CCl₄-treated mice but had limited effect on biliary fibrosis in Mdr2^-/- mice.³⁴ Models of liver or biliary fibrosis activate different mesenchymal cells, and thus local cellular niches need to be accounted for when designing fibrosis experiments.

Lineage tracing studies have revealed that DR pattern/morphology varies on the basis of the cell compartment that is injured. Indeed, it has been hypothesized that DR could arise from the biliary system, but also from hepatocytes. One study analyzed R26^tomHnf1b-CreER mice, which label bile ducts and periportal ductules (but not hepatocytes) with HNF1β, that were subjected to BDL, methylene dianiline (MDA), DDC, or choline-deficient, ethionine-supplemented (CDE) to evaluate DR in acute and chronic models. It was observed that DR arose from HNF1β⁺ biliary comportments in short-term (2–3 weeks) liver injury (BDL, MDA, and DDC); however, CDE feeding for 16 weeks had a small fraction of hepatocytes that co-expressed HNF1β.³⁵ Another study found that DR invading the parenchyma expressed biliary markers and formed de novo junctions that maintained the canaliculi after CDE feeding. Contrarily, in BDL and DDC models, DR was confined to the portal mesenchyme and formed pseudo-ductular structures.³⁶ Others found that thioacetamide (TAA) and DDC fed mice have a collapse of bile canaliculi that precedes DR; however, during recovery, reduced DR is paralleled with reconstruction of the bile canaliculi.³⁷ Therefore, DR may have a beneficial role regarding regeneration.

In 2 models of HPC activation, portal HPC expansion was associated with myofibroblast activation and laminin deposition; however, the source of laminin was not evaluated.³⁸ Others have found that PFs express laminin that supports HPC proliferation in mouse embryonic and neonatal liver.³⁹ Interestingly, glioma-associated oncogene (Gli1)+ PMCs surrounded intrahepatic bile ducts in BDL and DDC fed mice, but the DR in these models was extended into the parenchyma and surrounded by HSCs. However, the PMCs did not express HSC markers, indicating that they may be PF derived.²⁵ Interestingly, Gli1 facilitates cholangiocyte maturation and FN1 transcription, leading to ECM deposition in vitro.⁴⁰ In the dominant-negative TGF-β receptor II (dnTGFβRII) model of PBC, cholangiocytes had reduced expression of mature cholangiocyte markers, including secretin and its receptor, and restoration of mature cholangiocyte markers via secretin administration reduced biliary fibrosis and HSC presence.⁴¹ In vitro, HPCs differentiated to “mature” biliary-like cells through taurocholate (TCA) stimulation secreted chemokines that drive HSC chemotaxis.⁴² The origin and location of the DR are important for demarcating fibrosis patterns. DR in the parenchyma may interact predominantly with HSCs, whereas portal DR may interact with PFs and HSCs.

Biliary Senescence and TGF-β1: Lord of the SASPs

One characteristic of PSC and PBC is the presence of senescent cholangiocytes.⁵ K19-Mdm2^flox/floxtdTom^LSL mice are a model of tamoxifen-inducible cholangiocyte senescence, and after tamoxifen injection, these mice have elevated collagen deposition surrounding senescent bile ducts. Furthermore, cholangiocytes in these mice release SASPs, specifically TGF-β1, that recruit myofibroblasts.⁴³ Cholangiocytes from human PSC samples and cholestatic models exhibit telomerase damage, which was not seen in hepatocytes. The telomerase reverse transcriptase (TERT) was epigenetically repressed in senescent cholangiocytes, and overexpression of TERT decreased senescent and TGF-β1–mediated phenotypes of cholangiocytes in vitro. Therefore, selective genetic deletion of TERT from cholangiocytes may exacerbate biliary fibrosis.⁴⁴ The secretin/secretin receptor axis is enhanced in cholangiocytes in BDL mice, and silencing the secretin/secretin receptor axis reduced biliary senescence, which in turn reduced TGF-β1 levels and biliary fibrosis.⁴⁵ This phenotype was also observed in double knockout SR^-/-Mdr2^−/− mice.⁴⁶ Finally, blocking cholangiocyte senescence by p16 Vivo-Morpholino or senolytic (Fisetin) treatment in Mdr2^-/- mice reduced biliary fibrosis.⁴⁷ Overall, these studies underline the relationship between biliary senescence, SASPs secretion (eg, TGF-β1), and biliary fibrosis during cholestasis.

Bile Acids: Chasing the Great White Whale

Bile stasis in PBC and PSC can lead to changes in BA composition and accumulation that perpetuate liver damage.⁴⁸ Early studies found that all BAs at physiological concentrations induce HSC proliferation and activation in vitro,⁴⁹ and taurodeoxycholate (TDCA) and TCA induce PF proliferation and activation in precision cut liver slices from normal rats.⁵⁰ Hydrophobic BAs (eg, TCA, TDCA and lithocholate [LCA]) are considered damaging, whereas hydrophilic BAs (eg, UDCA) are considered protective.⁵¹ Supporting this, administration of hydrophilic BAs protects against immune cell infiltration and biliary fibrosis in Mdr2^-/- mice.⁵²^,⁵³ In addition, the hydrophobic BA chenodeoxycholate (CDCA) induces HSC activation and proliferation in vitro.⁵⁴ These studies suggest that alterations in BA hydrophobicity modulate myofibroblast activation; however, studies have suggested that dampening the overall BA pool may be key.⁵⁵ Inhibition of ileal apical sodium-dependent BA transporter (ASBT) reduced biliary BA output and increased fecal BA excretion, and this corresponded with reduced inflammation and biliary fibrosis in Mdr2^-/- mice.⁵⁶^,⁵⁷ Similarly, in dnTGFβRII mice secretin treatment enhances choleresis, thereby reducing hepatic BA levels, immune cell presence, and fibrosis.⁴¹ Reducing BA levels or hydrophobicity may be important for reversing biliary fibrosis.

Bile salt export pump (BSEP) is the main hepatic BA efflux transporter, but Bsep^-/- mice show a hydrophilic BA composition, and Mdr2^-/- mice crossed with Bsep^-/- mice show reduced immune cell infiltration and biliary fibrosis.⁵²^,⁵³ Na⁺-taurocholate co-transporting polypeptide (NTCP) is the major hepatic BA uptake transporter, and inhibition of NTCP reduces biliary damage, inflammation, and fibrosis in DDC fed and BDL mice; however, inhibition of NTCP aggravated inflammation and fibrosis in Mdr2^-/- mice,⁵⁸ indicating that targeting BA homeostasis differs between models. Introduction of human MDR3 (homolog to murine Mdr2), which regulates phospholipid secretion into bile, ameliorates inflammation and biliary fibrosis in Mdr2^-/- mice by reducing toxic BA levels.⁵⁹^,⁶⁰ Farnesoid X receptor (FXR) is a nuclear BA receptor that mediates BA synthesis and transporter expression, as well as inflammation. Tropifexor, a non-BA FXR agonist, reduces biliary fibrosis in piglets subjected to BDL for 14 days.⁶¹ A similar non-BA FXR agonist, EDP-305, decreased inflammation and fibrosis in Mdr2^-/- mice.⁶² Rat HSCs do not express BSEP,⁶³ primary human HSCs from fibrotic livers have increased NTCP expression,⁶⁴ and the role of FXR on human and mouse HSC activation is controversial.⁶⁵^,⁶⁶ Modulation of BA homeostasis may have direct effects on HSC and PF activation but also indirectly influences biliary fibrosis via modulation of inflammation.

BA-based drugs are currently used for PBC and PSC treatment. UDCA and obeticholic acid (OCA, ie, Ocaliva) are first- and second-line treatments, respectively, in PBC⁶⁷; however, only OCA shows beneficial effects on liver enzymes in PSC.⁶⁷^,⁶⁸ Cytochrome P450 family 2 subfamily c polypeptide 70 (Cyp2c70) knockout mice lack hydrophilic muricholic acids and display a more human-like BA pool. Cyp2c70^-/- mice showed spontaneous cholangiopathic features at 8 months of age, and UDCA treatment reduced inflammation and biliary fibrosis in Cyp2c70^-/- mice.⁶⁹ 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C₂₃ UDCA homologue that reduced inflammation and biliary fibrosis in Mdr2^-/- mice.⁷⁰^,⁷¹ Importantly, norUDCA has shown potential therapeutic benefit in PSC patients.⁷² BA-based therapies have important functions in reducing biliary fibrosis.

Endothelial Cells: The Angiogenesis Also Rises

Angiogenesis is the formation of new blood vessels and is noted in PBC and PSC samples.⁷³^,⁷⁴ In BDL rats, neovascularization is associated with biliary fibrosis.⁷⁵ Furthermore, hepatic vascular endothelial growth factor (VEGF) A (Vegfa/VEGFA) expression increases during fibrosis progression in CCl₄ treated, BDL, and Mdr2^-/- mice.⁷⁴^,⁷⁶^,⁷⁷ However, neutralizing antibody against VEGFA impairs fibrosis resolution after CCl₄ treatment through enhanced sinusoidal permeability.⁷⁸ Importantly, biliary fibrosis in cholangiopathies is associated with portal angiogenesis that may involve vascular endothelial cells as opposed to sinusoidal endothelial cells.⁷³^,⁷⁴ In line with this, DR in PSC is associated with enhanced fibrogenic gene expression and lies in close vicinity to angiogenic vessels.²⁸ It was observed that liver blood vessels (portal and central vessels and liver sinusoid) act differently during liver fibrogenesis. Blocking portal angiogenesis alleviates fibrosis, but the inhibition of both central angiogenesis and sinusoidal capillarization promotes liver fibrosis in CCl₄ treated mice.⁷⁹ This underlines the strong correlation between portal angiogenesis and liver fibrosis.

HSCs release angiogenic factors, including angiopoietin-1 (Angpt-1) and platelet-derived growth factor (PDGF), that drive angiogenesis.⁷⁵^,⁸⁰ Similarly, activated PFs secrete VEGFA, which promotes angiogenesis.⁸¹^,⁸² In turn, VEGFA and Angpt-1 promote HSC activation,⁸³ indicating a feedback loop between angiogenic and fibrogenic cells. Placental growth factor (PlGF) promotes angiogenesis in CCl₄ mice, and HSCs treated with PlGF in vitro have enhanced ECM synthesis.⁸⁴ Also, angiotensin enzyme 2 therapy directly blocks HSC activation and biliary fibrosis in Mdr2^-/- mice.⁸⁵ Activated PFs display both fibrogenic and angiogenic gene signatures, specifically split guidance ligand 2 (Slit2),²⁴ and Slit2 drives angiogenesis in DDC fed mice.⁸⁶ Portal myofibroblasts also drive angiogenesis through the release of VEGFA-enriched microparticles that signal to nearby endothelial cells.⁸² HSCs and PFs interact with endothelial cells to enhance angiogenesis, which, in turn, drives scar formation.

Aside from direct communication between endothelial and fibrogenic cells, angiocrine factors can regulate HSCs and PFs. Endothelin (ET) regulates the synthesis and secretion of TGF-β1 and VEGFA, and cholangiocytes with enhanced ET-A signaling initiate angiogenesis and fibrosis in Mdr2^-/- mice.⁷⁴ Vasohibin-1 (VASH-1) regulates VEGF through a negative feedback loop, and overexpression of VASH-1 reduced VEGF levels, pathologic angiogenesis, and biliary fibrosis in BDL mice.⁸⁷ These findings are significant because VEGF promotes pathologic, but not physiological, angiogenesis that is associated with fibrosis.⁸⁸ PSC is a risk factor for CCA,¹ and fibroblast-derived VEGFA/C promotes intravasation and early metastasis in CCA⁸⁹; therefore, VEGFA/C may be an important link between PSC and CCA development. It is apparent that angiogenic signaling can influence biliary fibrosis.

Immune Cells: For Whom the Fibrosis Tolls

Innate immunity is one of the first lines of defense against infection and broadly involves 3 cell types: granulocytes (ie, neutrophils, eosinophils, basophils, and mast cells [MCs]), monocytes/macrophages (eg, Kupffer cells [KCs, liver-resident macrophages]), and dendritic cells. If the innate immune response is unable to combat infection, the adaptive immune system is initiated. On first infection, the adaptive immune cells, T and B lymphocytes, perform cell- and antibody-mediated responses, and these signatures are memorized to allow for quicker responses if reinfection occurs.⁹⁰ In chronic liver diseases, both innate and adaptive immunity have been identified as drivers of fibrosis.⁹¹ Indeed, initial biliary fibrosis is characterized by portal inflammation (stage 1) but can expand into the periportal area along with inflammatory interface (stage 2). Next, portal-portal fibrosis bridges form with moderate/marked portal inflammation (stage 3), with eventual cirrhosis formation occurring (stage 4).⁹²^,⁹³ Here, we will describe how innate and adaptive immune cells can contribute to biliary fibrosis.

Monocytes and macrophages (MΦ) are phagocytes that maintain homeostasis through the clearance of cell debris and microbes. Hepatic MΦ, consisting of KCs and monocyte-derived macrophages (MoMΦ), exhibit heterogeneity and can contribute to fibrosis progression or resolution.⁹⁴ MoMΦ accumulate in PBC and PSC and are associated with DR, and MoMΦ infiltration adjacent to DR predicts advanced cirrhosis in PSC.⁹⁵^,⁹⁶ MΦ isolated from human liver fibrosis samples are pro-fibrotic and have overlapping pathways with HSCs, alluding to MΦ induction of HSC activation.⁹⁷ In BDL and DDC models, MoMΦ and KCs were pro-inflammatory, but elimination of KCs had no impact on biliary fibrosis.⁹⁸ Other research found KCs indispensable in BDL-induced biliary fibrosis.⁹⁹ MoMΦ are recruited by cholangiocyte released monocyte chemoattractant protein-1 (MCP-1), and blocking monocyte recruitment attenuated fibrosis in Mdr2^-/- mice.¹⁰⁰ MCP-1 further promotes pro-inflammatory phenotypes in KCs and recruits MoMΦ in BDL and Mdr2^-/- mice.¹⁰¹ HSCs, in turn, imprint pro-inflammatory signatures on MoMΦ.¹⁰² These studies suggest differential roles of infiltrating and resident MΦ on biliary fibrosis.

MCs release histamine and other mediators after their activation. In PSC livers, MCs reside in fibrotic areas and correlate with portal fibrosis.¹⁰³^,¹⁰⁴ Interestingly, HSCs produce stem cell factor, a MC chemoattractant, that induces MC homing in vitro.¹⁰⁵ One study found that in vitro co-culture of MCs with HSCs reduced HSC fibrogenesis¹⁰⁶; however, the HSC:MC ratio was 1:2.25, which is not appropriate for physiological standards. Selectively inhibiting MC-dependent H2 histamine receptor (HR) signaling reduces biliary fibrosis induced by MC injection,¹⁰⁷ and liver-specific down-regulation of H2HR reduces hepatic MC infiltration and biliary fibrosis in Mdr2^-/- mice.¹⁰⁸ Similarly, H1HR and H2HR antagonists diminish portal MC presence, as well as biliary fibrosis in Mdr2^-/- mice.¹⁰⁹ Last, when MC recruitment or activation is blocked, HSC number and biliary fibrosis are repressed in Mdr2^-/- mice and BDL models.110, 111, 112 Targeting MCs or MC-derived mediators, such as histamine, may be useful for regression of biliary fibrosis.

Neutrophils infiltrate the liver in acute infection or injury and act in a protective manner, but chronic liver disease leads to aberrant neutrophil signaling that may perturb damage.¹¹³ Human PSC samples have increased neutrophils in the portal region,¹¹⁴ and neutrophils are recruited early (3 hours after BDL).¹¹⁵ In DDC fed and CCl₄ treated mice, DR-associated neutrophils increase, and loss of neutrophils mitigates liver fibrosis.¹¹⁶ Early in vitro studies found that neutrophil production of reactive oxygen species promoted collagen synthesis in HSCs.¹¹⁷ In addition, neutrophils are a main source of interleukin 17 (IL-17) and IL-22, which show pro-fibrogenic effects on HSCs.¹¹⁸^,¹¹⁹ However, depletion of neutrophils after CCl₄ administration impairs fibrosis regression.¹²⁰ Also, neutrophils promote fibrosis resolution through matrix metalloproteinase secretion in BDL rats.¹²¹ Others have found that neutrophil attenuation had no effect on biliary fibrosis in BDL rats.¹²² Neutrophil involvement in biliary fibrosis is nuanced and may rely on the timing of infiltration and exposure to acute versus chronic damage.

In the spleen or lymph node, B cells, while in contact with cluster differentiation (CD)4 T helper (Th) cells, recognize antigen that causes them to differentiate to germinal center B cells or plasmablasts that can give rise to memory B cells or plasma cells, respectively. Plasma cells secrete antibodies in response to antigen, and B cells can produce cytokines through interaction with other immune cells.¹²³ PBC and PSC patients have increased numbers of B cells and plasma cells in the portal region,124, 125, 126, 127 and memory B cells are found in the fibrotic septa in PBC and PSC.¹²⁸ Mdr2^-/- mice have enhanced portal infiltration of pro-inflammatory B cells, which is attributed to increased expression of myeloid cell leukemia 1 (MCL1) in cholangiocytes. When Mdr2^-/- mice were treated with S63845, an MCL1 inhibitor, hepatic B cell number decreased along with biliary fibrosis.¹²⁹ Pro-inflammatory B cells increase in CCl₄ treated mice, and activated HSCs augmented B cell activity. Conversely, anti-B cell activating factor (BAFF) treatment had no effect on fibrosis in Mdr2^-/- mice; however, total depletion of B cells using anti-CD20 antibody treatment reduced hepatic fibrosis in Mdr2^-/- mice.¹³⁰ Genetic loss of B cells in dnTGFβRII mice led to enhanced pro-inflammatory markers, including IL-6 and tumor necrosis factor (TNF)-α,¹³¹ that are known to activate HSCs.¹³² Similarly, anti-CD20 antibody depletion of B cells in dnTGFβRII mice increased inflammation and IL-1α levels,¹³³ which are known to promote HSC proliferation.¹³² Others found that anti-CD20 antibody reduced hepatic inflammation in dnTGFβRII mice.¹³⁴^,¹³⁵ B cell modulation of biliary fibrosis is controversial and requires further investigation.

Naive T cells survey lymphoid organs and, after contact with an antigen presenting cell (APC), travel to the lymph nodes to (1) undergo clonal expansion, (2) become effector T cells (ie, Th cells, cytotoxic T lymphocytes [CTLs], regulatory T cells [Tregs]), and (3) traffic to the infected organ. Infection can produce memory T cells that recognize antigen on reinfection to become effector T cells.¹³⁶ T cells can promote HSC activation,¹³⁷ and HSCs cause apoptosis of T cells in fibrosis.¹³⁸ Interestingly, HSCs counteract APC initiated naive T-cell activation.¹³⁹ PBC patients have an increased number of Th cells and tissue-resident memory T cells (T_RM), whereas Tregs are decreased.¹²⁶^,¹⁴⁰^,¹⁴¹ Additionally, PSC patients have increased Th cells and CTLs near the bile ducts,¹⁴² and enhanced interferon γ signaling in PSC and Mdr2^-/- mice enhances CTL cytotoxicity and biliary fibrosis.¹⁴³ Th cell-derived IL-21, but not IL-17, enhanced fibrosis and CTL activity in dnTGFβRII mice.¹⁴⁴ In Mdr2^-/- and DDC fed mice, intrahepatic T_RM cells expanded, and inhibiting T_RM cell activity reduced biliary fibrosis.¹⁴⁵ NorUDCA attenuates CTL activity and biliary fibrosis in Mdr2^-/- mice.⁷⁰ Interestingly, loss of γδ T cells, a primitive T-cell subset, blocks liver fibrosis by inducing apoptosis in HSCs and inhibiting Th cell activity.¹⁴⁶ T cell heterogeneity is complex, and understanding how different T cells interact with PFs and HSCs will be essential for defining immunomodulation of biliary fibrosis.

Conclusion

In relation to biliary fibrosis, HSCs have historically been studied; however, research has identified PFs as an important contributor. Numerous studies have identified that PFs are the first fibrogenic cells to activate in cholestatic damage, thereby initiating biliary fibrosis, with recruitment of HSCs coming later. Indeed, the recruitment of HSCs later may be important in initiating bridging fibrosis. It is also key to understand that variations in damage initiation between BDL, DDC, Mdr2^-/-, and other models differentially impact PFs and HSCs. Discernable differences in fibrosis between models should be taken into consideration when designing experiments and analyzing samples. Additionally, variations in DR and its localization (eg, portal or parenchymal) can variably impact PFs and HSCs. This area of study can be further complicated when considering the different cellular sources that can give rise to DR and the role of senescent cholangiocytes and secreted SASPs on the activation/modulation of PFs and HSCs.

The buildup of BAs initiates both biliary and hepatocellular damage, which may variably induce fibrosis. The role of BA accumulation has been well-studied in HSCs; however, more work is needed in PFs. Unfortunately, BA receptor and transporter expression are controversial or unknown in HSCs and PFs. Portal angiogenesis is a pathologic feature known to promote fibrosis, and better demarcation of angiogenesis and how it interacts with HSCs and PFs is needed. Last, the portal niche can be inundated with infiltrating immune cells that show diversity. This complex immune response shapes cellular interactions, but the plethora of immune subsets makes teasing out mechanisms difficult.

Unsurprisingly, complex cellular interactions and diverse cell populations in cholangiopathies have varying impacts on biliary fibrosis (Figure 1). Studies thus far have identified potential therapeutics for PBC and PSC (Table 2); however, additional research will uncover novel therapeutic avenues. Although biliary fibrosis is multifarious, appreciating the nuance will be beneficial for furthering this area of study.

**Graphical representation of cellular crosstalk supporting biliary fibrosis.** DR can occur at the portal and parenchymal area, differentially facilitating biliary and bridging fibrosis. Different factors secreted from DR cells can contribute to fibrosis progression. Cholestasis leads to hepatic BA buildup, and various changes in BA excretion/secretion, transport, homeostasis, and interactions with PFs and HSCs can lead to biliary fibrosis. Senescent cholangiocytes have increased p16 expression, temolerase damage, and SASPs secretion, including TGF-β1, which stimulate activation of both PFs and HSCs during cholestasis. Angiogenesis is closely associated with biliary fibrosis, and different angiocrine signals between PFs, HSCs, and endothelial cells/LSECs can give rise to these pathologies. Last, immune cells infiltrate the liver during cholestasis and cholangiopathies, and the different immune subtypes have varying roles on PFs, HSCs, and biliary fibrosis. BA, bile acid; DR, ductular reaction; HSC, hepatic stellate cell; LSEC, lymphatic sinusoidal endothelial cell; PF, portal fibroblast; SASP, senescence-associated secretory phenotype; TGF-β, transforming growth factor β. Image made with BioRender.com.

Table 2.

Potential Therapeutic Agents for PBC and PSC

Drug class	Drug name/agent	Target/mode of action	Experimental model	Reference(s)
Anti-neoplastic	Bortezomib	Proteosome inhibition	Mdr2^-/- mice	32
Senolytic	Sec 5-27	SR antagonist	Mdr2^-/- mice	45
Senolytic	Fisetin	Anti-oxidation	Mdr2^-/- mice	47
Antifibrotic	FAP-specific inhibitor (FAPi) (S)-N-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-quinoline-4-carboxamide	Fibroblast activation protein (FAP)	CCl₄ and Mdr2^-/- mice	34
Bile acid–based	Tetrahydroxylated bile acids (THBAs)	Less toxic bile acid pool	Mdr2^-/- mice	52,53
	SC-435	Ileal ASBT inhibition	Cyp2c70^-/- and Mdr2^-/- mice	55,57
	A4250	Ileal ASBT inhibition	Mdr2^-/- mice	56
	Myrcludex B	NTCP inhibition	DDC, BDL, and Mdr2^-/- mice	58
	Synthetic human ABCB4 gene therapy	Restore ABCB4/MDR3	Mdr2^-/- mice	59,60
	Tropifexor	FXR agonist	BDL piglets	61
	EDP-305	FXR agonist	Mdr2^-/- mice	62
	Nor-UDCA	Anti-cholestatic and anti-inflammatory	Mdr2^-/- mice	70,71
Anti-angiogenic	Ambrisentan	ET-A antagonist	Mdr2^-/- mice	74
	Sorafenib	Kinase inhibitor	BDL rats	75
	MCR84	VEGF-neutralizing antibody	BDL mice	78
	αPlGF	PlGF-neutralizing antibody	CCl₄ mice	84
	AdVASH1 (synthetic human VASH1 gene therapy)	Restore vasohibin-1	BDL rats	87
Immunomodulatory	Cenicriviroc	CCR2/5 antagonist	BV6 injected mice	100
	Cromolyn sodium	Mast cell stabilizer	Mdr2^-/- mice and BDL rats	110,112
	Mepyramine and ranitidine	H1 and H2 histamine receptor antagonists	Mdr2^-/- mice	109
	SCH-527123	CXCR1/2 inhibitor	DDC mice	116
	S63845	MCL1 inhibitor	Mdr2^-/- mice	129
	Anti-CD20 antibody	B cell depletion	dnTGFβRII mice	134,135
	Anti-IFNγ antibody	IFNγ neutralization	Mdr2^-/- mice	143
	4-OI	Itaconate derivative	DDC and Mdr2^-/- mice	145

Open in a new tab

CD20, cluster of differentiation 20; CXCR1/2, C-X-C chemokine receptor type 1/2; Cyp2c70, cytochrome P450 family 2 subfamily c polypeptide 70; FAP, fibroblast activation protein; IFNγ, interferon γ; Mdr2/MDR3, multidrug resistance 2/3; SR, secretin receptor; THBA, tetrahydroxylated bile acid; VASH1, vasohibin 1.

Acknowledgments

CRediT Authorship Contributions

Ludovica Ceci (Writing – original draft, equal; Visualization, equal)

Eugenio Gaudio (Writing – review and editing, equal; Resources, equal; Funding acquisition, equal)

Lindsey Kennedy (Writing – original draft, lead; Visualization, lead; Resources, lead; Conceptualization, lead)

Footnotes

Conflicts of interest The authors disclose no conflicts.

Funding Supported by a Career Development Award-2 to LK (1IK2BX005306) from the United States Department of Veteran’s Affairs, Biomedical Laboratory Research and Development Service, and research project grants to EG from Sapienza, University of Rome. Portions of these studies were supported by resources at the Richard L. Roudebush VA Medical Center, Indianapolis, IN. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.

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PERMALINK

Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis

Ludovica Ceci

Eugenio Gaudio

Lindsey Kennedy

Abstract

Summary.

Hepatic Stellate Cells and Portal Fibroblasts: A Tale of Two Cells

Table 1.

Ductular Reaction: A Catch-22

Biliary Senescence and TGF-β1: Lord of the SASPs

Bile Acids: Chasing the Great White Whale

Endothelial Cells: The Angiogenesis Also Rises

Immune Cells: For Whom the Fibrosis Tolls

Conclusion

Figure 1.

Table 2.

Acknowledgments

CRediT Authorship Contributions

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis

Ludovica Ceci

Eugenio Gaudio

Lindsey Kennedy

Abstract

Summary.

Hepatic Stellate Cells and Portal Fibroblasts: A Tale of Two Cells

Table 1.

Ductular Reaction: A Catch-22

Biliary Senescence and TGF-β1: Lord of the SASPs

Bile Acids: Chasing the Great White Whale

Endothelial Cells: The Angiogenesis Also Rises

Immune Cells: For Whom the Fibrosis Tolls

Conclusion

Figure 1.

Table 2.

Acknowledgments

CRediT Authorship Contributions

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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