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 3

Evidence for the resistance of SOX9+ hepatocytes to cell death.

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Evidence for the resistance of SOX9+ hepatocytes to cell death. (A) C57B...
(A) C57BL/6 mice were treated with ConA for 48 and 72 hours; BrdU was given 2 hours before sacrifice. BrdU and SOX9 double staining of liver tissues (see representative images on the left) (n = 4). Percentages of BrdU+ hepatocytes were quantified (right). (B) WT and Sox9Hep–/– mice were treated with ConA for different times; BrdU was given 2 hours before sacrifice. Representative SOX9, H&E, and BrdU staining of liver tissues is shown (n = 4–5). Arrows indicate SOX9+ BDCs. (C) Percentages of necrotic area and percentages of Brdu+ hepatocytes from B were quantified. (D) Serum ALT levels were analyzed (n = 3–4). (E) C57BL/6 mice were treated with ConA for 48 hours. SOX9 and pSTAT3 staining of serial sections of liver tissues. Representative images are shown (n = 5). (F) WT, Sox9Hep–/–, and Notch2Hep–/– mice were treated with ConA for 48 hours. pSTAT3 was stained for the liver tissues (n = 5). (G) Percentages of pSTAT3+ hepatocytes from F were quantified (n = 5). Dashed lines indicate the borderlines or border areas of necrotic regions. Values in A, C, D, and G are represented as means ± SD. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (A, C, D and G). **P < 0.01; ***P < 0.001.