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

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 disease...

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Published in:Journal of Clinical Investigation 2023, Vol.133 (15)
Main Authors: Feng, Dechun, Xiang, Xiaogang, Guan, Yukun, Guillot, Adrien, Lu, Hongkun, Chang, Chingwen, He, Yong, Wang, Hua, Pan, Hongna, Ju, Cynthia, Colgan, Sean P, Tacke, Frank, Wang, Xin Wei, Kunos, George, Gao, Bin
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container_issue 15
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container_title Journal of Clinical Investigation
container_volume 133
creator Feng, Dechun
Xiang, Xiaogang
Guan, Yukun
Guillot, Adrien
Lu, Hongkun
Chang, Chingwen
He, Yong
Wang, Hua
Pan, Hongna
Ju, Cynthia
Colgan, Sean P
Tacke, Frank
Wang, Xin Wei
Kunos, George
Gao, Bin
description 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.sup.+] (SOX [9.sup.+]) 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.sup.+]) MoMFs that promoted necrotic removal and liver repair, while [Pdgfb.sup.+] MoMFs activated hepatic stellate cells (HSCs) to express [alpha]-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 [alpha]- smooth muscle actin-expressing HSCs to facilitate necrotic lesion resolution.
doi_str_mv 10.1172/JCI166954
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Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of complement 1q- positive ([C1q.sup.+]) MoMFs that promoted necrotic removal and liver repair, while [Pdgfb.sup.+] MoMFs activated hepatic stellate cells (HSCs) to express [alpha]-smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. 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subjects Gene expression
Genetic aspects
Health aspects
Immune response
Liver
Macrophages
Regeneration
Transcription factors
title Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models
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