Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models
Dechun Feng, … , George Kunos, Bin Gao
Dechun Feng, … , George Kunos, Bin Gao
Published June 20, 2023
Citation Information: J Clin Invest. 2023;133(15):e166954. https://doi.org/10.1172/JCI166954.
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Research Article Gastroenterology Hepatology

Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models

Abstract

The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages (MoMFs) were rapidly recruited to and encapsulated necrotic areas during immune-mediated liver injury and that this feature was essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activated the Jagged1/notch homolog protein 2 (JAG1/NOTCH2) axis to induce cell death–resistant SRY-box transcription factor 9+ (SOX9+) hepatocytes near the necrotic lesions, which acted as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of complement 1q–positive (C1q+) MoMFs that promoted necrotic removal and liver repair, while Pdgfb+ MoMFs activated hepatic stellate cells (HSCs) to express α–smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions, not only by removing necrotic tissues, but also by inducing cell death–resistant hepatocytes to form a perinecrotic capsule and by activating α-smooth muscle actin–expressing HSCs to facilitate necrotic lesion resolution.

Authors

Dechun Feng, Xiaogang Xiang, Yukun Guan, Adrien Guillot, Hongkun Lu, Chingwen Chang, Yong He, Hua Wang, Hongna Pan, Cynthia Ju, Sean P. Colgan, Frank Tacke, Xin Wei Wang, George Kunos, Bin Gao

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Figure 6

scRNA-Seq identifies 2 clusters of necrosis-associated MoMFs: C1q+ and Pdgfb+ MoMFs.

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scRNA-Seq identifies 2 clusters of necrosis-associated MoMFs: C1q+ and P...
(A and B) Liver MoMFs were isolated from ConA-treated mice (0-, 48-, and 72-hour time points). These cells were subjected to the 10x Genomics Chromium platform for scRNA-Seq. t-SNE plots of cells from naive (1,106 cells), ConA 48 hours after injection (ConA48) (8,541 cells), and ConA 72 hours after injection (3,575 cells) are shown in A. Heatmap of the signature genes of C1q+ macrophages (cluster 2) and Pdgfb+ macrophages (cluster 4) is shown in B. (C and D) C57BL/6 mice were treated with ConA for 48 or 72 hours. Liver tissues were doubly stained with C1Q/IBA1, CTSB/IBA1, LGMN/IBA1, and APOE/IBA1 (C, n = 5), and PDGFB/IBA1 (D, n = 5). Dashed lines indicate the border areas of necrotic regions. Arrowheads indicate IBA+ cells with PDGFB expression. Representative images and quantitation are shown. Values in C and D are represented as means ± SD. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (C and D). ***P < 0.001.