Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models
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
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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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 4

aHSCs aggregate in the border areas of necrosis at the late-stage recovery of live injury.

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aHSCs aggregate in the border areas of necrosis at the late-stage recove...
(A and B) C57BL/6 mice were treated with ConA. BrdU was given 2 hours before sacrifice. Liver tissues were collected and stained with desmin/α-SMA and desmin/BrdU. Representative images are shown in A (n = 4). Quantification of aHSCs and proliferating HSCs in noninjured area, inside necrotic area, and border area in A is shown in B. (C) Liver tissues from ConA-treated mice were stained with desmin/YAP/α-SMA or desmin/PMLC. Representative triple- or double-staining images are shown (n = 5). Quantitation of the percentages of YAP+Desmin+ and pMLC+Desmin+ in border areas was performed. (D) Liver tissues from ConA-treated mice were stained with IBA1/ECE1 (n = 4–5). Dashed lines indicate the border areas of necrotic regions. Quantitation of ECE1+IBA1+/total IBA1+ cells in border areas was performed. Values in B–D are represented as means ± SD. Statistical significance was assessed using 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (B–D). **P < 0.01; ***P < 0.001.