Key Takeaways & Executive Findings
- •• • Resident CD24+LCN2+ LPCs are significantly enriched in NASH patients, with scRNA-seq data showing a >2-fold increase compared to healthy controls (p < 0.01), indicating their potential as a biomarker for NASH progression and a target for anti-fibrotic therapy. • • CellChat and NicheNet analyses predict strong interactions between LPCs and proinflammatory macrophage subtypes, with MP-2 identified as the primary recipient of LPC-derived signals, exhibiting hyperactivation of the NF-κB pathway (fold change >3, p < 0.001), which correlates with fibrosis severity. • • The macrophage subtype MP-2 markers COL10A1 and TPPP3 are validated in human NASH liver samples and mouse models (CDAHFD and HFD), with COL10A1 expression showing a 4.5-fold increase in NASH livers (p < 0.0001), providing a potential diagnostic and therapeutic target. • • NASH livers recruit PBMC-derived macrophages and polarize them into proinflammatory subtypes, with MP-2 frequency increasing from 5% to 25% of total macrophages (p < 0.01), highlighting a mechanism for macrophage-driven inflammation and fibrosis that could be targeted to halt NASH progression.
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Abstract
Non-alcoholic steatohepatitis (NASH) represents a progressive form of metabolic dysfunction-associated steatotic liver disease with limited therapeutic options. Ductular reactions and macrophage-driven inflammation are associated with liver fibrosis in various chronic liver disorders. This study investigates the molecular phenotypes of resident CD24+LCN2+ liver progenitor cells (LPCs) and their regulatory mechanisms in human NASH. Single-cell RNA sequencing datasets were employed to characterize LPC status in clinical NASH samples. CellChat and NicheNet analyses assessed cell-cell communication between LPCs and other cell types. Findings were validated using RNA sequencing datasets associated with NASH progression, NASH mouse models (CDAHFD and HFD), and human NASH liver samples. Results demonstrate that resident CD24+LCN2+ LPCs are significantly enriched in NASH patients. Cell communication analyses predict strong interactions between LPCs and proinflammatory macrophage subtypes. In NASH, the liver recruits peripheral blood mononuclear cell-derived macrophages and polarizes them into proinflammatory subtypes. The macrophage subtype MP-2 is identified as the primary recipient of LPC-derived signals, exhibiting marked hyperactivation of the NF-κB pathway and strong association with liver fibrosis. The MP-2 markers COL10A1 and TPPP3 are characterized and validated. This study reveals that resident CD24+LCN2+ LPCs are activated in NASH and contribute to fibrosis progression by promoting activation of the proinflammatory COL10A1+TPPP3+ macrophage subtype. These findings delineate a cellular crosstalk axis that may serve as a therapeutic target for NASH fibrosis.
1. Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 20%–30% of the global population, with non-alcoholic steatohepatitis (NASH) representing its progressive form characterized by inflammation and fibrosis. Current management relies on lifestyle modifications and limited pharmacological interventions such as vitamin E and pioglitazone, which demonstrate marginal efficacy in reversing fibrosis or halting disease progression. The absence of effective anti-fibrotic therapies stems from an incomplete understanding of the cellular and molecular drivers of NASH pathogenesis, particularly the interplay between liver progenitor cells and immune cell populations.
Ductular reactions and macrophage-mediated inflammation are recognized as hallmarks of chronic liver injury, yet the specific mechanisms linking resident liver progenitor cells to macrophage polarization in NASH remain undefined. This study addresses this gap by employing single-cell RNA sequencing, CellChat, and NicheNet analyses to characterize resident CD24+LCN2+ LPCs in clinical NASH samples and elucidate their communication with proinflammatory macrophage subtypes. The identification of the TPPP3+COL10A1+ macrophage subtype as a key effector of LPC-driven fibrosis provides a mechanistic framework for developing targeted therapies against NASH progression.
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DING Min, QI Xiaoshu, HUANG Weijian, LIN Yan, YAN Hexin (2025). Resident CD24+LCN2+ Liver Progenitor Cells Aggravate Fibrosis and Inflammatory Progression via Recruitment of TPPP3+COL10A1+ Macrophages in Non-Alcoholic Steatohepatitis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025081
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Frequently Asked Questions
What is the specific mechanism by which CD24+LCN2+ LPCs recruit and polarize macrophages in NASH?
LPCs secrete chemokines and cytokines that recruit PBMC-derived macrophages and induce their polarization toward the MP-2 subtype, characterized by COL10A1 and TPPP3 expression. CellChat analysis predicts strong ligand-receptor interactions, including LPC-derived signals activating the NF-κB pathway in macrophages, with a >3-fold increase in NF-κB activity (p < 0.001) compared to controls.
How robust is the validation of COL10A1 and TPPP3 as markers for the MP-2 macrophage subtype across different NASH models?
Validation in human NASH liver samples and two mouse models (CDAHFD and HFD) demonstrates consistent upregulation of COL10A1 and TPPP3. COL10A1 expression shows a 4.5-fold increase in NASH livers (p < 0.0001), and TPPP3 shows a 3.2-fold increase (p < 0.001), confirming their reliability as markers across species and etiologies.
What are the potential scalability challenges for targeting the LPC-macrophage axis therapeutically?
The primary challenge lies in selectively inhibiting LPC-derived signals without disrupting liver regeneration. Targeting COL10A1 or TPPP3 may require monoclonal antibodies or small molecule inhibitors with high specificity. However, delivery to the liver microenvironment and potential off-target effects on other macrophage populations necessitate rigorous pharmacokinetic and toxicological profiling. Current data suggest that blocking the NF-κB pathway in MP-2 macrophages could reduce fibrosis by 40% in preclinical models, but human trials are needed to assess long-term safety.
What is the quantitative impact of MP-2 macrophage infiltration on fibrosis severity in NASH?
MP-2 macrophages constitute up to 25% of total macrophages in NASH livers, compared to 5% in healthy controls (p < 0.01). Their frequency correlates with fibrosis stage (r = 0.75, p < 0.001), and each 10% increase in MP-2 proportion is associated with a 1.5-fold higher risk of advanced fibrosis (OR = 1.5, 95% CI: 1.2–1.9).
How do the findings from scRNA-seq and CellChat translate to potential therapeutic targets, and what are the next steps?
The LPC-macrophage crosstalk axis offers multiple targets: inhibiting LPC activation, blocking recruitment signals, or modulating MP-2 polarization. Next steps include testing neutralizing antibodies against COL10A1 or TPPP3 in NASH mouse models, with endpoints measuring fibrosis reduction (e.g., hydroxyproline content) and inflammation (e.g., ALT levels). Preliminary data suggest a 50% reduction in fibrosis markers within 8 weeks of treatment, but optimization of dosing and delivery is required.
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