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Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice

BACKGROUND AND AIMS: Mitogen‐activated protein kinase kinase (MKK) 7 and MKK4 are upstream activators of c‐Jun NH(2)‐terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepa...

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Autores principales: Ooshio, Takako, Yamamoto, Masahiro, Fujii, Kiyonaga, Xin, Bing, Watanabe, Kenji, Goto, Masanori, Okada, Yoko, Suzuki, Akira, Penninger, Josef M., Nishina, Hiroshi, Nishikawa, Yuji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252741/
https://www.ncbi.nlm.nih.gov/pubmed/32969030
http://dx.doi.org/10.1002/hep.31565
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author Ooshio, Takako
Yamamoto, Masahiro
Fujii, Kiyonaga
Xin, Bing
Watanabe, Kenji
Goto, Masanori
Okada, Yoko
Suzuki, Akira
Penninger, Josef M.
Nishina, Hiroshi
Nishikawa, Yuji
author_facet Ooshio, Takako
Yamamoto, Masahiro
Fujii, Kiyonaga
Xin, Bing
Watanabe, Kenji
Goto, Masanori
Okada, Yoko
Suzuki, Akira
Penninger, Josef M.
Nishina, Hiroshi
Nishikawa, Yuji
author_sort Ooshio, Takako
collection PubMed
description BACKGROUND AND AIMS: Mitogen‐activated protein kinase kinase (MKK) 7 and MKK4 are upstream activators of c‐Jun NH(2)‐terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepatocyte proliferation, the functional role of MKK7 in the liver has remained unclear. APPROACH AND RESULTS: Here, we examined phenotypic alterations in liver‐specific or hepatocyte/hematopoietic cell–specific MKK7 knockout (KO) mice, which were generated by crossing MKK7(LoxP/LoxP) with albumin–cyclization recombination (Alb‐Cre) or myxovirus resistance protein 1–Cre mice, respectively. The livers of Alb‐Cre(−/+) MKK7(LoxP/LoxP) mice developed without discernible tissue disorganization. MKK7 KO mice responded normally to liver injuries incurred by partial hepatectomy or injection of CCl(4). However, tissue repair following CCl(4)‐induced injury was delayed in MKK7 KO mice compared with that of control mice. Furthermore, after repeated injections of CCl(4) for 8 weeks, the liver in MKK7 KO mice showed intense fibrosis with increased protractive hepatocyte proliferation, suggesting that MKK7 deficiency might affect regenerative responses of hepatocytes in the altered tissue microenvironment. MKK7 KO hepatocytes demonstrated normal proliferative activity when cultured in monolayers. However, MKK7 KO significantly suppressed branching morphogenesis of hepatocyte aggregates within a collagen gel matrix. Microarray analyses revealed that suppression of branching morphogenesis in MKK7 KO hepatocytes was associated with a reduction in mRNA expression of transgelin, glioma pathogenesis related 2, and plasminogen activator urokinase‐type (Plau); and forced expression of these genes in MKK7 KO hepatocytes partially recovered the attenuated morphogenesis. Furthermore, hepatocyte‐specific overexpression of Plau rescued the impaired tissue repair of MKK7 KO mice following CCl(4)‐induced injury. CONCLUSIONS: MKK7 is dispensable for the regenerative proliferation of hepatocytes but plays important roles in repair processes following parenchymal destruction, possibly through modulation of hepatocyte–extracellular matrix interactions.
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spelling pubmed-82527412021-07-12 Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice Ooshio, Takako Yamamoto, Masahiro Fujii, Kiyonaga Xin, Bing Watanabe, Kenji Goto, Masanori Okada, Yoko Suzuki, Akira Penninger, Josef M. Nishina, Hiroshi Nishikawa, Yuji Hepatology Original Articles BACKGROUND AND AIMS: Mitogen‐activated protein kinase kinase (MKK) 7 and MKK4 are upstream activators of c‐Jun NH(2)‐terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepatocyte proliferation, the functional role of MKK7 in the liver has remained unclear. APPROACH AND RESULTS: Here, we examined phenotypic alterations in liver‐specific or hepatocyte/hematopoietic cell–specific MKK7 knockout (KO) mice, which were generated by crossing MKK7(LoxP/LoxP) with albumin–cyclization recombination (Alb‐Cre) or myxovirus resistance protein 1–Cre mice, respectively. The livers of Alb‐Cre(−/+) MKK7(LoxP/LoxP) mice developed without discernible tissue disorganization. MKK7 KO mice responded normally to liver injuries incurred by partial hepatectomy or injection of CCl(4). However, tissue repair following CCl(4)‐induced injury was delayed in MKK7 KO mice compared with that of control mice. Furthermore, after repeated injections of CCl(4) for 8 weeks, the liver in MKK7 KO mice showed intense fibrosis with increased protractive hepatocyte proliferation, suggesting that MKK7 deficiency might affect regenerative responses of hepatocytes in the altered tissue microenvironment. MKK7 KO hepatocytes demonstrated normal proliferative activity when cultured in monolayers. However, MKK7 KO significantly suppressed branching morphogenesis of hepatocyte aggregates within a collagen gel matrix. Microarray analyses revealed that suppression of branching morphogenesis in MKK7 KO hepatocytes was associated with a reduction in mRNA expression of transgelin, glioma pathogenesis related 2, and plasminogen activator urokinase‐type (Plau); and forced expression of these genes in MKK7 KO hepatocytes partially recovered the attenuated morphogenesis. Furthermore, hepatocyte‐specific overexpression of Plau rescued the impaired tissue repair of MKK7 KO mice following CCl(4)‐induced injury. CONCLUSIONS: MKK7 is dispensable for the regenerative proliferation of hepatocytes but plays important roles in repair processes following parenchymal destruction, possibly through modulation of hepatocyte–extracellular matrix interactions. John Wiley and Sons Inc. 2021-05-28 2021-06 /pmc/articles/PMC8252741/ /pubmed/32969030 http://dx.doi.org/10.1002/hep.31565 Text en © 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Ooshio, Takako
Yamamoto, Masahiro
Fujii, Kiyonaga
Xin, Bing
Watanabe, Kenji
Goto, Masanori
Okada, Yoko
Suzuki, Akira
Penninger, Josef M.
Nishina, Hiroshi
Nishikawa, Yuji
Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice
title Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice
title_full Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice
title_fullStr Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice
title_full_unstemmed Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice
title_short Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice
title_sort hepatocyte mitogen‐activated protein kinase kinase 7 contributes to restoration of the liver parenchyma following injury in mice
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252741/
https://www.ncbi.nlm.nih.gov/pubmed/32969030
http://dx.doi.org/10.1002/hep.31565
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