The hepatic portal area, encompassing the portal vein (PV), hepatic artery (HA) and bile duct triad, acts as a hub for blood inflow, bile drainage and inter-organ communication. Through a highly organized cellular network, it underlies immune homeostasis and tissue architecture [
1,
2]. In liver disease, this region is a prominent site of pathological remodeling, including portal fibrosis and ductular reaction (DR), characteristics of cholangiopathies that are ultimately shared across virtually all chronic liver diseases [
2,
3].
FETAL DEVELOPMENT OF THE PORTAL TRIAD
The foregut endoderm, receiving signals, i.e., bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs) and retinoic acid, from the cardiac mesoderm and septum transversum mesenchyme (STM), invades the STM and forms hepatoblasts, the bipotent progenitors of hepatocytes and cholangiocytes, which together with mesenchymal and endothelial populations form the liver bud.
Endothelium derived from the sinus venosus, an embryonic venous cavity connected to the developing heart, and possibly also from the endoderm, migrates into the STM and together with the vitelline and umbilical veins, ultimately contributes to the hepatic vasculature. The STM gives rise to distinct populations of the liver mesenchyme, including the precursors of portal fibroblasts (PFs), mesothelial cells, and hepatic stellate cells (HSCs). Single-cell analyses have also identified a hepatoblast-derived epithelial-mesenchymal hybrid progenitor population, termed hepatomesenchymal cells [
4].
Periportal hepatoblasts progressively organize into the ductal plate surrounding the portal veins [
5]. Ductal plate remodeling involves focal dilatations, which generate nascent bile ducts, while angiogenic cues derived from developing cholangiocytes and adjacent hepatoblasts coordinate hepatic artery formation and maturation of the portal triad unit [
6]. During late developmental stages, autonomic nerve fibers enter the liver through the hilum and postnatally extend along the portal tract network towards the liver periphery [
7]. Disruption of these coordinated developmental programs can result in congenital biliary disorders, including ductal plate malformations and neonatal cholangiopathies such as biliary atresia [
8,
9].
PORTAL CELLS IN LIVER HOMEOSTASIS
In the mature liver, the portal area supports hepatic homeostasis through the coordinated functions of epithelial, mesenchymal, vascular and immune cell populations. Cholangiocytes lining the bile ducts ensure bile collection and modification, and retain regenerative and repair potential [
10]. Portal mesenchymal cells [
11,
12] include vascular smooth muscle cells (VSMCs), which regulate vascular tone, and PFs, which maintain periportal tissue integrity through extracellular matrix (ECM) production while regulating cholangiocyte proliferation,13 and contributing to immune homeostasis through PF-like Mes-2 subsets implicated in macrophage maturation [
14].
The portal vascular compartment comprises the HA and the peribiliary vascular plexus (PBVP), which provide oxygen supply, the PV, which conveys gut-derived nutrients and immune cues, and lymphatics (Ly), which support lymphatic drainage and immune surveillance, all lined by specialized endothelial cells (ECs) [
11,
15].
Portal immune cells protect the gut-liver axis by limiting pathogen dissemination, presenting innocuous antigens to maintain immune tolerance, and clearing circulating microbes and debris [
2,
16]. Mucosal-associated invariant T (MAIT) cells contribute to periportal immune surveillance and can be activated by biliary epithelial cells in an MHC-related protein 1 (MR1)-dependent manner [
17]. Periportal macrophage subsets further reinforce this barrier; for example, MARCO
+ macrophages capture gut-derived pathogen-associated molecular patterns (PAMPs) to limit immune activation and neutrophil infiltration [
18]. Bile duct lipid-associated macrophages (BD-LAMs) may arise through local lipid exposure and are less responsive than Kupffer cells (KCs) to
in vivo TLR4 stimulation [
19]. Additionally, liver portal area-associated macrophages (LPAMs), a distinct subset of portal macrophages residing in the portal area, particularly around the PV, capture hepatocyte-derived antigens and directly interact with sympathetic nerve fibers, suggesting a role in portal neuro-immune regulation [
20].
PORTAL CELLULAR RESPONSES TO LIVER INJURY
The portal cellular response to injury initially promotes tissue repair, but persistent insult drives inflammatory periportal remodeling with immune-cell recruitment, DR and portal fibrosis, key pathological features of biliary injury and fibrosis progression [
3].
Upon chronic injury, PFs, a heterogeneous cell population, expand and differentiate into portal myofibroblasts (PMFs) [
12,
21-
23] expressing α-smooth muscle actin (α-SMA). Recent work identified
Clec3b+ PFs as the primary source of PMFs following activation
via a KLF4/periostin axis and as key effectors of portal fibrosis. Evidence indicates that PMFs interact with HSCs, promoting their survival through SLIT2 secretion12 and their myofibroblastic activation through periostin secretion [
22]. PMF-derived signals drive portal fibrosis progression into the hepatic lobule and ultimately contribute to cirrhosis [
12,
21]. PFs can also transform into cancer-associated fibroblasts (CAFs), promoting intrahepatic cholangiocarcinoma progression [
24].
Immune-cell dynamics further shape periportal remodeling. Neutrophils rapidly accumulate in the periportal area post-injury, exerting a “dual role”: they promote steatosis, inflammation, and HSC-driven fibrosis, but also facilitate repair
via reparative macrophage polarization and ECM degradation [
25]. MAIT cells are also implicated in cholangiopathies, with increasing evidence linking them to biliary immune activation, DR and fibrosis [
26]. Resident KCs decline in liver injury, whereas monocyte-derived macrophages (MoMFs) expand and diversify into context-dependent inflammatory, fibrogenic and reparative states. Among these populations, IBA1
+ MoMFs markedly accumulate upon biliary injury and interact with cholangiocytes, triggering DR, activating HSCs and PFs, and exacerbating periportal injury and fibrosis [
27]. TREM2
+ LAM-like macrophages respond to cholangiocyte- and hepatocyte-derived cues and undergo context-dependent functional switching, thereby amplifying inflammation and promoting tissue repair or fibrosis during chronic liver injury [
28,
29].
TECHNOLOGICAL PROGRESS IN PORTAL AREA RESEARCH
Portal area research relies on foundational cell isolation techniques, as well as innovative analytical tools and in vitro models. Isolation of cells from the bilio-vascular tree has enabled studies of portal-enriched cell populations, while breakthroughs in single-cell sequencing [
12,
22], spatial transcriptomics [
30], genetic cell fate tracing or ablation [
23], and high-resolution imaging (e.g., two-photon intravital imaging and confocal live-cell time-lapse imaging) [
13,
18] have further revealed detailed cellular composition, spatial architecture, and intercellular signaling.
In vitro models are increasingly able to recapitulate key features of the portal microenvironment. Early organoid systems lacked the full periportal multicellular architecture, whereas subsequent co-culture models have been able to reconstitute selected ductal-mesenchymal interactions [
13]. Liver assembloids incorporating all essential portal components faithfully mimic
in vivo physiology and fibrosis, enabling mechanistic studies (gene knockout, targeted cell manipulation) of portal contribution to liver diseases [
31]. Extending this technology to humans, patient-derived periportal assembloids recapitulate key features of murine models while incorporating expandable patient-specific cellular components for studies of liver disease [
32].
FOOTNOTES
-
Authors’ contribution
Fanrong Kong and Lin Lei conceived the Snapshot. Fanrong Kong prepared the manuscript and figure. Xinwei Li, Chantal Housset, Sara Lemoinne, and Lin Lei revised the manuscript and the figure.
-
Acknowledgements
This work was supported by the National Natural Science Foundation of China (U24A20454). Selected graphical elements in the figures were created using BioRender.com.
-
Conflicts of Interest
Sara Lemoinne reports consulting work for Mirum, Ipsen, Amgen, and Servier; lectures for Ipsen, Mirum, and Echosens; and congress participation by invitation from Mirum, Ipsen, AbbVie, and Gilead. The other authors declare no conflicts of interest.
Abbreviations
bile duct lipid-associated macrophages
cancer-associated fibroblasts
liver portal area-associated macrophages
mucosal-associated invariant T
monocytederived macrophages
peribiliary vascular plexus
septum transversum mesenchyme
vascular smooth muscle cells
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