Monocyte-Derived Macrophages Orchestrate Multiple Cell-Type Interactions To Repair Necrotic Liver Lesions in Disease Models

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

Publication Date

8-1-2023

Journal

Journal of Clinical Investigation

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.

Keywords

Humans, Actins, Liver, Hepatocytes, Macrophages, Hepatic Stellate Cells, Necrosis, Liver Neoplasms