Ductular reaction as a spatial fibrogenic niche: cholangiocyte-macrophage-fibroblast crosstalk in chronic liver disease.
- 1Department of General Hepatobiliary Surgery, Ganmei Hospital Affiliated to Kunming Medical University, Kunming, China.
- 2Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract
Ductular reaction-the expansion of reactive bile ductules at the portal-parenchymal interface-has traditionally been interpreted as a proliferative or regenerative response of the biliary epithelium to chronic injury. Here we argue that this histological phenomenon is better understood as a spatial fibrogenic niche: a physically organized, self-reinforcing microenvironment in which reactive cholangiocytes, macrophages, and matrix-producing mesenchymal cells engage in bidirectional signaling that converts repair into fibrosis. We integrate single-cell and spatial transcriptomic evidence showing that reactive cholangiocytes act as a signaling hub, secreting TGF-β, PDGF, CCL2, CXCL chemokines, IL-6, osteopontin, and Hedgehog ligands; that recruited and tissue-resident macrophages amplify this axis; and that portal fibroblasts and hepatic stellate cells close a feed-forward loop by depositing extracellular matrix and growth factors that sustain the niche. We propose that a cholangiocyte-macrophage-fibroblast feed-forward loop, stabilized by chemokine-driven recruitment, TGF-β-centered fibrogenesis, mechanical feedback, and senescence, underlies ductular-associated fibrosis across cholestatic and metabolic liver diseases. Targeting the pathological organization of this niche-rather than any single cell type-may offer a new therapeutic framework for chronic liver fibrosis.
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BibTeX
@article{wang2026ductular,
title = {{Ductular reaction as a spatial fibrogenic niche: cholangiocyte-macrophage-fibroblast crosstalk in chronic liver disease.}},
author = {Kun Wang and Linjun Li and Xiangkun Mei and Hongqiang Gao},
journal = {Frontiers in medicine},
year = {2026},
month = oct,
doi = {10.3389/fmed.2026.1987203},
url = {https://europepmc.org/article/MED/42923744},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ductular reaction as a spatial fibrogenic niche: cholangiocyte-macrophage-fibroblast crosstalk in chronic liver disease.
AU - Kun Wang
AU - Linjun Li
AU - Xiangkun Mei
AU - Hongqiang Gao
PY - 2026
DA - 2026/10/08
JO - Frontiers in medicine
DO - 10.3389/fmed.2026.1987203
UR - https://europepmc.org/article/MED/42923744
AB - Ductular reaction-the expansion of reactive bile ductules at the portal-parenchymal interface-has traditionally been interpreted as a proliferative or regenerative response of the biliary epithelium to chronic injury. Here we argue that this histological phenomenon is better understood as a spatial fibrogenic niche: a physically organized, self-reinforcing microenvironment in which reactive cholangiocytes, macrophages, and matrix-producing mesenchymal cells engage in bidirectional signaling that converts repair into fibrosis. We integrate single-cell and spatial transcriptomic evidence showing that reactive cholangiocytes act as a signaling hub, secreting TGF-β, PDGF, CCL2, CXCL chemokines, IL-6, osteopontin, and Hedgehog ligands; that recruited and tissue-resident macrophages amplify this axis; and that portal fibroblasts and hepatic stellate cells close a feed-forward loop by depositing extracellular matrix and growth factors that sustain the niche. We propose that a cholangiocyte-macrophage-fibroblast feed-forward loop, stabilized by chemokine-driven recruitment, TGF-β-centered fibrogenesis, mechanical feedback, and senescence, underlies ductular-associated fibrosis across cholestatic and metabolic liver diseases. Targeting the pathological organization of this niche-rather than any single cell type-may offer a new therapeutic framework for chronic liver fibrosis.
SN - 2296-858X
ER -