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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) |
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container_title | Journal of Clinical Investigation |
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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 |
format | report |
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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.</description><identifier>ISSN: 0021-9738</identifier><identifier>DOI: 10.1172/JCI166954</identifier><language>eng</language><publisher>American Society for Clinical Investigation</publisher><subject>Gene expression ; Genetic aspects ; Health aspects ; Immune response ; Liver ; Macrophages ; Regeneration ; Transcription factors</subject><ispartof>Journal of Clinical Investigation, 2023, Vol.133 (15)</ispartof><rights>COPYRIGHT 2023 American Society for Clinical Investigation</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>776,780,4476,27902</link.rule.ids></links><search><creatorcontrib>Feng, Dechun</creatorcontrib><creatorcontrib>Xiang, Xiaogang</creatorcontrib><creatorcontrib>Guan, Yukun</creatorcontrib><creatorcontrib>Guillot, Adrien</creatorcontrib><creatorcontrib>Lu, Hongkun</creatorcontrib><creatorcontrib>Chang, Chingwen</creatorcontrib><creatorcontrib>He, Yong</creatorcontrib><creatorcontrib>Wang, Hua</creatorcontrib><creatorcontrib>Pan, Hongna</creatorcontrib><creatorcontrib>Ju, Cynthia</creatorcontrib><creatorcontrib>Colgan, Sean P</creatorcontrib><creatorcontrib>Tacke, Frank</creatorcontrib><creatorcontrib>Wang, Xin Wei</creatorcontrib><creatorcontrib>Kunos, George</creatorcontrib><creatorcontrib>Gao, Bin</creatorcontrib><title>Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models</title><title>Journal of Clinical Investigation</title><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. 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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.</abstract><pub>American Society for Clinical Investigation</pub><doi>10.1172/JCI166954</doi></addata></record> |
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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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