Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis

Abstract Mammalian cardiomyocytes substantially lose proliferative capacity immediately after birth, limiting adult heart regeneration after injury. However, clinical myocarditis appears to be self-limiting with tissue-reparative properties. Here, we investigated the molecular mechanisms underlying...

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Autores principales:	Akimitsu Miyawaki, Masanori Obana, Yusuke Mitsuhara, Aya Orimoto, Yusuke Nakayasu, Tomomi Yamashita, So-ichiro Fukada, Makiko Maeda, Hiroyuki Nakayama, Yasushi Fujio
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f1472f5aafeb436c997d794e33a49a20
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spelling	oai:doaj.org-article:f1472f5aafeb436c997d794e33a49a202021-12-02T15:06:07ZAdult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis10.1038/s41598-017-01426-82045-2322https://doaj.org/article/f1472f5aafeb436c997d794e33a49a202017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01426-8https://doaj.org/toc/2045-2322Abstract Mammalian cardiomyocytes substantially lose proliferative capacity immediately after birth, limiting adult heart regeneration after injury. However, clinical myocarditis appears to be self-limiting with tissue-reparative properties. Here, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model. Three weeks after EAM induction (EAM3w), cardiac tissue displayed infiltration of inflammatory cells with cardiomyocyte apoptosis. However, by EAM5w, the myocardial damage was remarkably attenuated, associated with an increase in cardiomyocytes that were positively stained with cell cycle markers at EAM3w. Cardiomyocyte fate mapping study revealed that the proliferating cardiomyocytes primarily derived from pre-existing cardiomyocytes. Signal transducer and activator of transcription 3 (STAT3) was robustly activated in cardiomyocytes during inflammation, accompanied by induction of interleukin-6 family cytokines. Cardiomyocyte-specific ablation of STAT3 gene suppressed the frequency of cycling cardiomyocytes in the recovery period without influencing inflammatory status, resulting in impaired tissue repair and cardiac dysfunction. Finally, microarray analysis revealed that the expression of regeneration-related genes, metallothioneins and clusterin, in cardiomyocytes was decreased by STAT3 gene deletion. These data show that adult mammalian cardiomyocytes restore regenerative capacity with cell cycle reentry through STAT3 as the heart recovers from myocarditis-induced cardiac damage.Akimitsu MiyawakiMasanori ObanaYusuke MitsuharaAya OrimotoYusuke NakayasuTomomi YamashitaSo-ichiro FukadaMakiko MaedaHiroyuki NakayamaYasushi FujioNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Akimitsu Miyawaki Masanori Obana Yusuke Mitsuhara Aya Orimoto Yusuke Nakayasu Tomomi Yamashita So-ichiro Fukada Makiko Maeda Hiroyuki Nakayama Yasushi Fujio Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis
description	Abstract Mammalian cardiomyocytes substantially lose proliferative capacity immediately after birth, limiting adult heart regeneration after injury. However, clinical myocarditis appears to be self-limiting with tissue-reparative properties. Here, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model. Three weeks after EAM induction (EAM3w), cardiac tissue displayed infiltration of inflammatory cells with cardiomyocyte apoptosis. However, by EAM5w, the myocardial damage was remarkably attenuated, associated with an increase in cardiomyocytes that were positively stained with cell cycle markers at EAM3w. Cardiomyocyte fate mapping study revealed that the proliferating cardiomyocytes primarily derived from pre-existing cardiomyocytes. Signal transducer and activator of transcription 3 (STAT3) was robustly activated in cardiomyocytes during inflammation, accompanied by induction of interleukin-6 family cytokines. Cardiomyocyte-specific ablation of STAT3 gene suppressed the frequency of cycling cardiomyocytes in the recovery period without influencing inflammatory status, resulting in impaired tissue repair and cardiac dysfunction. Finally, microarray analysis revealed that the expression of regeneration-related genes, metallothioneins and clusterin, in cardiomyocytes was decreased by STAT3 gene deletion. These data show that adult mammalian cardiomyocytes restore regenerative capacity with cell cycle reentry through STAT3 as the heart recovers from myocarditis-induced cardiac damage.
format	article
author	Akimitsu Miyawaki Masanori Obana Yusuke Mitsuhara Aya Orimoto Yusuke Nakayasu Tomomi Yamashita So-ichiro Fukada Makiko Maeda Hiroyuki Nakayama Yasushi Fujio
author_facet	Akimitsu Miyawaki Masanori Obana Yusuke Mitsuhara Aya Orimoto Yusuke Nakayasu Tomomi Yamashita So-ichiro Fukada Makiko Maeda Hiroyuki Nakayama Yasushi Fujio
author_sort	Akimitsu Miyawaki
title	Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis
title_short	Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis
title_full	Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis
title_fullStr	Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis
title_full_unstemmed	Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis
title_sort	adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through stat3 in the healing process of myocarditis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f1472f5aafeb436c997d794e33a49a20
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Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis

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